Brain Research Bulletin 110 (2015) 1–13

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Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull

Review

Acetylcholine, GABA and neuronal networks: A working hypothesis for compensations in the dystrophic brain Erez James Cohen a , Eros Quarta a , Gianluca Fulgenzi b,c , Diego Minciacchi a,∗ a b c

Department of Clinical and Experimental Medicine, Physiological Sciences Section, University of Florence, Florence, Italy Laboratory of Experimental Pathology, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy Neural Development Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA

a r t i c l e

i n f o

Article history: Received 27 May 2014 Received in revised form 2 October 2014 Accepted 6 October 2014 Available online 16 October 2014 Keywords: Duchenne muscular dystrophy Neuronal networks mdx Network oscillations Acetylcholine

a b s t r a c t Duchenne muscular dystrophy (DMD), a genetic disease arising from a mutation in the dystrophin gene, is characterized by muscle failure and is often associated with cognitive deficits. Studies of the dystrophic brain on the murine mdx model of DMD provide evidence of morphological and functional alterations in the central nervous system (CNS) possibly compatible with the cognitive impairment seen in DMD. However, while some of the alterations reported are a direct consequence of the absence of dystrophin, others seem to be associated only indirectly. In this review we reevaluate the literature in order to formulate a possible explanation for the cognitive impairments associated with DMD. We present a working hypothesis, demonstrated as an integrated neuronal network model, according to which within the cascade of events leading to cognitive impairments there are compensatory mechanisms aimed to maintain functional stability via perpetual adjustments of excitatory and inhibitory components. Such ongoing compensatory response creates continuous perturbations that disrupt neuronal functionality in terms of network efficiency. We have theorized that in this process acetylcholine and network oscillations play a central role. A better understating of these mechanisms could provide a useful diagnostic index of the disease’s progression and, perhaps, the correct counterbalance of this process might help to prevent deterioration of the CNS in DMD. Furthermore, the involvement of compensatory mechanisms in the CNS could be extended beyond DMD and possibly help to clarify other physio-pathological processes of the CNS. © 2014 Elsevier Inc. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cognitive impairment in DMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Intelligence quotient (IQ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Dystrophin isoforms and the mdx model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alterations and compensations in the cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Expression of dystrophin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Cerebellar role in cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Alterations due to lack of dystrophin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Role of ACh in the cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Possible compensatory mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2 2 2 3 3 3 3 3 3 3 4

Abbreviations: ACh, acetylcholine; AChE, aceteylcholinesterase; CB, calbindin; CNS, central nervous system; DG, dentate gyrus; DMD, Duchenne muscular dystrophy; IPSCs, inhibitory postsynaptic currents; IQ, intelligence quotient; mAChRs, muscarinic ACh receptors; mIPSCs, miniature inhibitory postsynaptic currents; LTD, long term depression; LTP, long term potentiation; NO, nitric oxide; PV, parvalbumin. ∗ Corresponding author at: Department of Clinical and Experimental Medicine, Physiological Sciences Section, University of Florence, Viale Morgagni 63, I-50134 Florence, Italy. Tel.: +39 0552751605; fax: +39 0554379506. E-mail address: diego@unifi.it (D. Minciacchi). http://dx.doi.org/10.1016/j.brainresbull.2014.10.004 0361-9230/© 2014 Elsevier Inc. All rights reserved.

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Alterations and compensations in the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.1. Expression of dystrophin in the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.2. Alterations due to lack of dystrophin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.3. Role of ACh in the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.4. Network level correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.5. Induced neurogenesis and differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.6. Overview of the suggested integrated model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Alterations and compensations in the cerebral cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.1. Expression of dystrophin in the cerebral cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.2. Alterations due to lack of dystrophin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.3. Role of ACh in the cerebral cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.4. Network level correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1. Introduction Duchenne muscular dystrophy (DMD), an X-linked recessive genetic disease arising from a mutation of the dystrophin gene, is characterized by muscle degeneration and is often associated with cognitive deficits. The gene’s product, dystrophin, is found in the proximity of the inner surface of membranes and is typically present in muscles (Zubrzycka-Gaarn et al., 1988); it is thought to mediate calcium homeostasis and to maintain membrane integrity (Head, 1993). Duchenne’s original observation, of cognitive impairment in some of his patients (Duchenne, 1868), gave rise to an ongoing discussion on whether or not DMD and cognition were related. At present, the notion of a casual contingency between dystrophin and cognitive impairment could safely be discarded. There is growing evidence that the expression of dystrophin is selectively distributed within the CNS with abundance in the cerebellum and hippocampus (Chelly et al., 1988; Huard and Tremblay, 1992; Kim et al., 1992; Lidov et al., 1990, 1993; Knuesel et al., 1999; Kueh et al., 2011; Snow et al., 2013), and the absence of dystrophin in the CNS was suggested to primarily affect synaptic transmission (Blake and Kröger, 2000). Though a comprehensive explanation for the CNS alterations due to the lack of dystrophin remains elusive, some alterations have been extensively characterized. Anderson et al. (2002), have summarized the alterations of the dystrophic brain derived from histological, biochemical and electrophysiological evidences. Some results suggest that most of the alterations associated with cognitive impairment are related to mutations of the specific dystrophin isoforms Dp140 and Dp71 (Moizard et al., 1998, 2000). Further studies suggest the possible involvement of other isoforms (Giliberto et al., 2004; Taylor et al., 2010; D’Angelo et al., 2011; Tozawa et al., 2012). A variety of studies have focused their attention mainly on the disruption of neuronal function, yet there is evidence that some brain functions (such as working and reference memory) are not compromised despite the lack of dystrophin (Sesay et al., 1996; Vaillend et al., 1998; Hinton et al., 2007). An investigation of these salvaged functions had revealed that, in the corresponding brain areas, the alterations are similar to those seen in processes of neuronal plasticity (Kulak and Sobaniec, 2004; Vaillend et al., 2004). Some of these alterations are associated with sustained enhancement of synaptic efficacy and of neuronal excitability (Vaillend et al., 2004), whereas others seem to counteract eventual excitotoxicity (as suggested by Del Tongo et al., 2009), all of which appear to be initiated in an attempt to re-establish a compromised equilibrium. Considering these findings, we infer that neuronal compensations in DMD may occur to some extent, whilst their tropism could reflect area-specific physiognomies. This could suggest that while some areas possess, at least initially, the ability to compensate for the deficit of dystrophin, and therefore demonstrate a slower deterioration, other areas are less privileged.

In this paper, we review some of the alterations reported in the CNS due to lack of dystrophin that might stand on the basis of the cognitive impairments described for DMD, focusing mainly on the cholinergic and GABAergic systems seeing that their role has not been appropriately addressed in current literature. Although the expression of dystrophin was demonstrated also in various cortical areas and in the amygdala (Lidov et al., 1993; Sekiguchi et al., 2009), we chose to limit our discussion only to the three most studied structures (i.e. cerebellum, hippocampus, and the cerebral cortex). We present a working hypothesis according to which within the cascade of events leading to cognitive impairments in DMD there are compensatory mechanisms aimed to maintain functional stability via perpetual adjustments of excitatory and inhibitory components. Such ongoing compensatory response creates continuous perturbations that disrupt neuronal functionality in terms of network efficiency. 2. Cognitive impairment in DMD Cognitive impairment is a clinical feature of DMD, as it affects about one-third of the patients (Prosser et al., 1969; Cotton et al., 2001; Pereira et al., 2005). The DMD patient population was found to have an intelligence quotient (IQ) shifted downward approximately one standard deviation below the normal range (Felisari et al., 2000). Cognitive impairment is not progressive and does not correlate with the stage or the severity of the disease. It seems to affect verbal more than non-verbal intelligence (Billard et al., 1992; Moizard et al., 1998; Cotton et al., 2001). 2.1. Development The age of onset is not well defined seeing that already in early stages of development some of the DMD patients exhibit language delay which is not influenced by factors such as mother’s intelligence, family environment and socio-cultural level (Smith et al., 1990). Such language delay was studied evaluating the beginning of first words (delayed in 42% of patients), beginning of sentence formation (delayed in 49% of patients), and beginning of reading (delayed in 94% of patients) (Cyrulnik et al., 2007). Moreover, not only language is affected at young age, a delay in neurological development was evident in all the 4 domains (motor, language, adaptive and personal–social) as demonstrated by Cyrulnik et al. (2008). 2.2. Intelligence quotient (IQ) The DMD patient population was found to have an intelligence quotient (IQ) shifted downward approximately one standard deviation below the normal range (Felisari et al., 2000). Various studies have shown that verbal IQ is more affected than executive IQ (Prosser et al., 1969; Marsh and Munsat, 1974; Cotton et al., 2001),

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although some studies have failed to demonstrate a significant difference between verbal and executive IQ (Donders and Taneja, 2009; Wingeier et al., 2011). Within the DMD group with cognitive impairment (around a third of patients) it was shown that 79.3% suffer from slight mental retardation (IQ between 50 and 70), 19.3% suffer from moderate mental retardation (IQ between 35 and 50), 1.1% suffer from serious mental retardation (IQ between 20 and 35), and 0.3% suffer from profound mental retardation (IQ < 20) (Cotton et al., 2001). Moreover, patients lacking the Dp140 dystrophin isoform exhibited greater cognitive problems (Wingeier et al., 2011). 2.3. Memory Patients with DMD exhibited a worse performance in attention and memory, abstract thinking, and academic achievements, which seems to be characterized by a selective deficit in verbal working memory skills (Hinton et al., 2000, 2001). It was later shown that both short- and long-term memory are affected (Wicksell et al., 2004). Specifically, the DMD profile appears to be related to deficits in the ability of keeping verbal working memory “on-line” and accessible for further information processing, an ability in which the cerebellum has been implicated (Cyrulnik and Hinton, 2008). Though the results derived from neuropsychological studies of the specific cognitive deficits are somewhat inconsistent, the majority indicates that expressive and receptive language, and visuospatial processing are preserved (Hinton et al., 2000, 2001). 2.4. Dystrophin isoforms and the mdx model While the above mentioned cognitive impairments were non attributed to any specific dystrophin isoform, the presence of moderate but specific memory and attention deficits in all DMD patients, regardless of whether they are of high or low intellectual function (Hinton et al., 2000), suggests a role for the full-length dystrophin (Dp427) which is commonly lost in all patients. Although this paper will focus mainly on the mutations that specifically affect the full-length dystrophin, it is important to mention that mutations affecting the genomic region of Dp71 and Dp140 have been associated with higher incidence and most severe profiles of cognitive alterations (Moizard et al., 1998, 2000; Felisari et al., 2000; Daoud et al., 2009). Most of our current understanding of dystrophin function derives from studies of the Dp427-deficient mdx mouse. The mdx mice display various behavioral abnormalities such as: abnormal motor behavior and coordination (Grady et al., 2006), reduced activity in open spaces (Vaillend et al., 2004), and enhanced defensive freezing responses after restraint suggesting altered amygdala function (Sekiguchi et al., 2009). Mdx mice also show slower learning in bar-pressing tasks and impaired retention performance at long delays in tests involving recognition and spatial memories (Muntoni et al., 1991; Vaillend et al., 1995, 1999, 2004; Vaillend and Ungerer, 1999). While encoding of new experiences and learning capabilities are globally preserved (Sesay et al., 1996; Vaillend et al., 1998), such alterations are suggestive for a selective role for full-length dystrophin in the consolidation or expression of specific forms of long-term memory (Perronnet and Vaillend, 2010). 3. Alterations and compensations in the cerebellum While the cerebellum is not the first structure one would study in a patient with cognitive impairments, the abundant expression of dystrophin in the cerebellum and the cerebellar involvement in various cognitive processes have led to the hypothesis that DMD is in fact a cerebellar disorder (Cyrulnik and Hinton, 2008).

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3.1. Expression of dystrophin Expression of dystrophin within the cerebellum is limited to the Purkinje cells (Huard and Tremblay, 1992; Lidov et al., 1990, 1993), and more accurately, studies have revealed high density of dystrophin at postsynaptic structures (Lidov et al., 1990; Kim et al., 1992). Dystrophin is not uniformly distributed in the murine cerebellum being more expressed in the lateral cerebellum compared with the vermis (Snow et al., 2013). It was also shown that dystrophin typically co-localized with GABAA receptors in the soma of Purkinje cells as suggested by immuno-labeling (Knuesel et al., 1999). 3.2. Cerebellar role in cognition In cognition, the lateral parts of the cerebellum are considered of being involved in an expansion of cerebro-cerebellar loops (Leiner et al., 1991, 1993). It was demonstrated that the cerebellum receives inputs from various association areas of the cerebral cortex and can influence cerebral activity by projecting back to these areas (Allen and Tsukahara, 1997; Ito, 1984; Middleton and Strick, 1994). Cyrulnik and Hinton (2008) in their review of cerebellar involvement in DMD have summarized the various evidences, gathered from neuroimaging, neuroanatomical, and neurophysiological studies, supporting the role of the cerebellum in cognition with focus on verbal working memory and reading. 3.3. Alterations due to lack of dystrophin Considering the molecular interactions of dystrophin with various intracellular and extracellular components, some of the cerebellar alterations seen in DMD and in the mdx model are to be expected; such alterations include the reduction of GABAA clusters at postsynaptic densities (Knuesel et al., 1999). Studies also support the notion that loss of dystrophin reduces the number of functional GABAA receptors at synapses but increases the level of extra-synaptic GABAA receptors in cerebellar Purkinje cells in mdx mice. This abnormality may be due to a defect in the sequestration of GABAA receptors at postsynaptic sites in the absence of dystrophin (Kueh et al., 2008, 2011). Furthermore, it was shown that while postsynaptically mediated long-term depression (LTD) is reduced in the cerebellar Purkinje cells of mdx mice, the presynaptically mediated short-term plasticity is unaffected (Anderson et al., 2004). Less intuitive is the significant increase in choline-containing compounds (up to three times higher) in the cerebellum and the hippocampus associated with DMD in boys younger than 13 years (Rae et al., 1998). Other areas of the brain did not show any significant increase at this age group. An increase in choline-containing compounds is also seen in boys older than 17 years in the prefrontal cortex (Kato et al., 1997). Rae et al. (2002), in their paper on biochemical abnormalities of the mdx brain, have suggested that these alterations in the cerebellum and the hippocampus could imply a compensation mechanism. 3.4. Role of ACh in the cerebellum In the CNS, acetylcholine (ACh) functions as neurotransmitter/neuromodulator and is known to be involved in various neuronal processes including plasticity (Rasmusson, 2000). Although cholinergic transmission within the cerebellum was not extensively studied, evidences do exist regarding the effects of ACh on various cerebellar components. In one of the earlier studies on cerebellar cholinergic transmission, Crepel and Dhanjal (1982) have demonstrated that the use of atropine abolished fast spikes evoked in Purkinje cells by synaptic or electrical stimulation. In another

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Fig. 1. A diagram of the cerebellar circuitry. The pathways shown are considered to be involved in the cholinergic transmission. Orange indicates sites in which alterations were reported in the mdx mouse (see in text). Blue dots indicate sites of expression of full-length dystrophin (Dp427); note that in the mossy fibers expression of dystrophin was only suggested (Lidov et al., 1993) and not demonstrated. (For interpretation of the references to color in text, the reader is referred to the web version of this article.)

study it was reported that the predominant fiber system in the cerebellum that might use ACh as a transmitter or a co-transmitter is formed by mossy fibers originating in the vestibular nuclei and innervating the nodulus and ventral uvula (Jaarsma et al., 1997). As for the effect of ACh on the lateral cerebellum, although current literature is still lacking, evidence for a cholinergic activity in these parts was demonstrated by measuring the activity of choline acetyltransferase (Asin et al., 1984). Therefore, while the effect of ACh within the lateral cerebellum remains dubious and should be studied in more depth, it cannot be excluded. Though the implications of the increased choline reported in DMD (Rae et al., 1998, 2002) are not clear, alterations in the cerebellar cholinergic system, such as reduction of nicotinic activity, have been associated with neurodevelopmental disorders such as autism (Lee et al., 2002). Several structures of the CNS provide ACh input to the cerebellum; these structures include: vestibular nuclei, raphe nuclei, peduncolopontine tegmental nuclei, and nucleus reticularis gigantocellularis (Libster and Yarom, 2013). The role of ACh is also depicted in the description of the cerebellar circuitry of Geurts et al. (2003). Excitatory input via mossy fibers (ACh and glutamate mediated) acts on the granular cells and unipolar brush cells within the granular layer of the cerebellum. The granular cells, in turn, excite the Purkinje cells via parallel fibers. Furthermore, mossy fibers excite inhibitory Golgi cells, which, in turn, inhibit the unipolar brush cells and the granular cells and, consequently, the parallel fibers (GABA mediated), creating a feed-forward loop. The Golgi cells are also stimulated by the parallel fibers, thus creating a feedback loop. Direct inhibition of the Purkinje cells is mediated via the basket and stellate cells; these cells release GABA that acts on the GABAA receptors of the Purkinje cells. Basket and stellate cells are stimulated by the parallel fibers. It is worth mentioning that other transmitters as glycine and nitric oxide (NO) are also involved in the cerebellar circuits (Geurts et al., 2003). Moreover, ACh was shown to act directly on the cerebellar nuclei, Purkinje cells, mossy and parallel fibers, and to a smaller degree on the stellate and Golgi cells (Jaarsma et al., 1995, 1997; Libster and Yarom, 2013). From this model it is visible that ACh could affect various components of the cerebellar circuitry (Fig. 1).

In a recent study it was reported that the activation of muscarinic ACh receptors (mAChRs) has a suppressive effect on long term potentiation (LTP) induction at synapses between parallel fibers and Purkinje cell. ACh decreases the likelihood of induction for different forms of LTP, potentially enhancing the overall penetrance of LTD. It was suggested that mAChRs activation selectively targets presynaptic and postsynaptic LTP mechanisms and, though not directly, LTD penetrance could be enhanced indirectly by the prevention of coincident potentiation. Thus, cholinergic signaling in the cerebellum suppresses presynaptic LTP to prevent an upregulation of transmitter release that opposes the reduction of postsynaptic responsiveness (Rinaldo and Hansel, 2013). 3.5. Possible compensatory mechanisms Considering these findings, cerebellar cholinergic potentiation in DMD might represent a compensatory mechanism aimed to restore correct functionality of the cerebellum by modulation of Purkinje excitation/inhibition and by facilitating LTD. It was demonstrated that a principal function of the highly recurrent networks is to generate persistent activity (Cossart et al., 2003), supporting the assumption that networks tend to maintain a preferential state of activity. Interestingly, a general reduction in acetylcholinesterase (AChE) within the CNS of mdx mice was reported (Comim et al., 2011), suggesting that central augmentation of the cholinergic tone is not limited to the cerebellum. Anderson et al. (2003) have reported that loss of dystrophin causes a reduction in the GABAergic response in Purkinje neurons. In principle, a loss of GABAergic inputs should reduce the resting potential of Purkinje neurons; instead, the opposite was measured experimentally. Snow et al. (2014) showed that Purkinje neurons from the lateral and vermal areas of the cerebellum have distinct basal electrophysiological properties unrelated to synaptic inputs. This regional differentiation of Purkinje cells is lost in mdx cerebella, with the lateral Purkinje neurons becoming hyperpolarized thus reducing spontaneous firing. Previously the same group asserted that there are regional differences in dystrophin densities among the vermal and the lateral cerebella with immuno-staining

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being more intense in the lateral than the vermal cerebella (Snow et al., 2013). While such hyperpolarization could be explained by a shift in the tonic current due to an increase in extrasynaptic GABA receptors in the mdx mouse Purkinje cells, brought about by the inability of the receptors to be localized at the postsynaptic membrane region (Kueh et al., 2008, 2011), it could also represent a compensatory modification of the resting potential of Purkinje neurons which, interestingly, is more accentuated in the lateral Purkinje neurons compared to vermal neurons. 4. Alterations and compensations in the hippocampus 4.1. Expression of dystrophin in the hippocampus The abundant hippocampal expression of dystrophin is well documented (Lidov et al., 1990, 1993). Immunoreactivity to fulllength dystrophin is present in the CA1 and CA3 regions and is uniform in pyramidal cells, reduced in the stratum radiatum and oriens, and absent in the stratum lacunosum molecolare. In the dentate gyrus (DG) immunoreactivity to full-length dystrophin was absent (Lidov et al., 1990, 1993), although in a later study the presence of the dystophin isoform Dp71 was observed also in DG (Górecki and Barnard, 1995). Furthermore, an extensive colocalization with GABAA receptors was observed in the soma and dendrites of hippocampal pyramidal cells but the axon initial segment, which is rich in GABAA receptor subunits, was negative for dystrophin staining (Knuesel et al., 1999; Brünig et al., 2002). Colocalization was associated with the ␣2, ␥2 subunits of the GABAA receptors (Knuesel et al., 1999). It was shown that the subunit ␥2 is fundamental for expression of GABAA receptors in synapses of the developing or adult hippocampus (Gunther et al., 1995; Essrich et al., 1998; Schweizer et al., 2003). 4.2. Alterations due to lack of dystrophin As with the alterations seen in the cerebellum associated with DMD and mdx, a great reduction in postsynaptic GABAA clustering and an increase of choline-containing compounds were also reported in the hippocampus (Knuesel et al., 1999; Rae et al., 2002). Along with the decrease in postsynaptic GABAA clustering, a marked increase of parvalbumin (PV) expressing GABAergic interneurons was reported in mdx mice, with greatest increase in the DG and CA1 regions (Del Tongo et al., 2009). This observation is consistent with a previous finding of increased frequency of miniature inhibitory postsynaptic currents (mIPSCs) in CA1 (Graciotti et al., 2008). In the attempt to establish the cause of such increased GABAergic spontaneous activity Graciotti et al. (2008) quantified the number of inhibitory synapses in the soma of pyramidal neurons of CA1 hippocampal area, finding no differences between mdx and wild type hippocampi. They concluded that the increased GABAergic spontaneous activity in mdx CA1 seems to be due to an increased presynaptic activity. Activation of nicotinic ACh receptors by ACh (1 mM) or choline (10 mM) enhances the frequency of GABAergic postsynaptic currents in both pyramidal neurons and CA1 interneurons (Alkondon and Albuquerque, 2001). Extended alterations of the cholinergic transmission in mdx hippocampi regarding receptors (Ghedini et al., 2012), ACh release (Parames et al., 2014), and performance in a memory consolidation test (Coccurello et al., 2002) have been described, sustaining the possibility of a presynaptic modulation of GABA release. In addition, some of these structural parameters diverged in 12 months old versus 4 months old mdx mice (Ghedini et al., 2012), thereby suggesting aging-dependent processes. The authors have also suggested that these alterations could represent a compensatory response to the deficit in GABAA receptors.

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Miranda et al. (2011), have reported an alteration in presynaptic ultrastructure in excitatory hippocampal synapses within CA1 of mice lacking Dp427 or Dp71. Specifically, the group reported an increase in density of morphologically docked vesicles and a reduction in vesicle size in mice lacking Dp427; this was demonstrated in the proximal, but not distal, radiatum within CA1. Interestingly, the majority of the vesicles were clustered in the reserve pool suggesting an abnormal shift of the vesicle distribution from the reserve to docked pools in the proximal CA1 synapses. While the expression of full-length dystrophin was demonstrated to be selective to the postsynaptic density (Lidov et al., 1990; Kim et al., 1992), such alterations in the presynaptic ultrastructure (Miranda et al., 2011) are suggestive for a secondary adaptation or compensation due to lack of dystrophin. In an earlier work, the same group had reported an increased number of axodendritic synapses on CA1 pyramidal neurons of mdx mice (Miranda et al., 2009). Despite the fact that inhibitory inputs on pyramidal cell dendrites are not the most relevant for tonic inhibition of CA1 pyramidal cells, an increase in number of these synapses may indeed represent a compensatory event to counterbalance the reported rarefaction of GABAA receptors in soma of mdx CA1 pyramidal neurons (Knuesel et al., 1999). Early studies of the DG and CA1 regions in mdx have reported no alterations regarding LTP and spatial learning (Sesay et al., 1996; Vaillend et al., 1998). A further investigation revealed an abnormal enhancement of LTP in CA1 with persistent excitability after LTP induction, and was suggested of being the result of an altered synaptic plasticity due to a lower threshold for NMDA activation (Vaillend et al., 2004). In this latter study, impairments in longterm memory for spatial memory and object recognition were also reported, yet no impairments for acquisition and short-term memory were observed. The abnormal enhancement of LTP was later shown to be reversed using small nuclear RNAs, modified to encode antisense sequences expressed from adeno-associated viral vectors, inducing skipping of the mutated exon 23 and thus rescuing the expression of a functional dystrophin-like product in both muscle and nervous tissues. Specifically in the brain a partial restoration of dystrophin was reported (25.2 ± 8% of re-expression two months after intrahippocampal vector injection; Dallérac et al., 2011). From a biochemical point of view, studies have reported an increased sensitivity to hypoxia-induced loss of synaptic transmission in hippocampal pyramidal neurons of mdx (Mehler et al., 1992). This was further investigated by exposing mdx hippocampal tissue slices, kept at different concentrations of glucose, to an irreversible hypoxic failure; mdx slices kept at 10 mM glucose demonstrated more susceptibility to hypoxia when compared with controls, whereas those kept at 4 mM glucose demonstrated less susceptibility compared with controls (Godfraind et al., 2000). These findings reflect a decreased bioenergetics buffering capacity (Anderson et al., 2002). Moreover, alterations within the hippocampus of mdx are also seen in the mitochondria, these included a decreased activity of complex I of the mitochondrial respiratory chain and an increased of the mitochondrial creatine kinase (Tuon et al., 2010). GABAA receptor activation had been shown to exacerbate oxygen–glucose deprivation-induced neuronal injury (Muir et al., 1996). 4.3. Role of ACh in the hippocampus As stated before, an increase in choline-containing compounds was reported also in the hippocampi of both DMD and mdx. The major source of ACh to the hippocampus is the medial septal nucleus (Dutar et al., 1995), although other populations of cholinergic interneurons were also identified within the hippocampus (Fig. 2; Frotscher et al., 2000). It was shown that trains of stimuli delivered at 10–20 Hz, within the range at which putative septal cholinergic cells discharge during theta rhythm (Brazhnik and

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Fig. 2. A diagram of the hippocampal circuitry (partially redrawn from Ascoli and Atkeson, 2005). Orange indicates sites in which alterations were reported in the mdx mouse (see in text). Blue dots indicate sites of expression of full-length dystrophin (Dp427). Note that in the dentate gyrus only expression of Dp71 was reported, but not that of full-length dystrophin. DG: dentate gyrus; EC: entorhinal cortex (II, III, and IV–VI = second, third, and fourth–sixth layers, respectively), GABA PmC: GABAergic polymorphic cells, GC: granular cells, MoPP: molecular perforant pathway, PC: pyramidal cells, Sub: subiculum. (For interpretation of the references to color in text, the reader is referred to the web version of this article.)

Fox, 1999), result in a robust recruitment of a mAChR-mediated synaptic response in interneurons and pyramidal neurons (Morton and Davies, 1997). mAChRs mediate excitement of pyramidal neurons by modulating ionic conductance directly and indirectly (Dodd et al., 1981; Cole and Nicoll, 1983; Halliwell, 1990). Activation of mAChRs was shown to have a double effect on GABAergic interneurons, directly increasing the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) while at the same time depressing monosynaptically evoked IPSCs and the frequency of mIPSCs (Behrends and ten Bruggencate, 1993). Activation of mAChRs was also shown to enhance LTP within the DG (Burgard and Sarvey, 1990) whilst enhancing or depressing LTP within CA3 pyramidal neurons (Maeda et al., 1993). Moreover, administration of cholinergic antagonists had been associated with memory impairment (Gorman et al., 1994). Interestingly, Yoshihara and colleagues reported a reduced density of AMPA kainic-acid receptor in several brain areas of mdx mice compared to controls, whereas the muscarinic cholinergic receptors had comparable densities (Yoshihara et al., 2003). Such selective alteration could imply a preferential conservation of the cholinergic activity, representing a further illustration of the importance of the cholinergic tone. Moreover, it is worth noting that even though Yoshihara et al. (2003) found no quantitative differences in muscarinic receptor density, other parameters of cholinergic activity (e.g. receptor facilitation, nicotinic cholinergic receptors, current amplitude and frequency, etc.) were not evaluated and may undergo modifications.

4.4. Network level correlates The possible effects of ACh at the neuronal component level are on the basis of various phenomena at the network level. Activation of ACh receptors induces a range of synchronized oscillatory responses in hippocampal slices (MacVicar and Tse, 1989; Fisahn et al., 1998; Shimono et al., 2000); these oscillatory states require intact excitatory and inhibitory circuits, being disrupted by blockade of fast glutamatergic and GABAergic neurotransmission (Cobb and Davies, 2005). Furthermore, mAChR-driven intrinsic theta frequency oscillations have been reported in specific interneurons (Chapman and Lacaille, 1999), which, in turn, synchronize

pyramidal cell activity through phasic inhibition (Cobb et al., 1995). Buzsáki (2002), in his review of theta oscillations in the hippocampus, provided various findings supporting the role of cholinergic excitation in oscillatory states and their tight interactions with GABAergic inhibition; he also described the tight relationship between theta oscillations and induction of LTP. It was later described that LTP in hippocampal neurons is accompanied by spatially widespread changes in intrinsic oscillatory dynamics and excitability (Narayanan and Johnston, 2007), thus suggesting a bidirectional relationship between LTP and oscillatory activity. In another study it was stated that despite large changes in excitability in a sub-second scale, long-term firing rates of individual neurons are relatively constant, resulting in a stable mean hippocampal output over time (Buzsáki et al., 2002). Evidences indicate that during certain patterns of activity such as active exploratory behavior, in which theta hippocampal oscillations are superimposed by gamma oscillations, there is an increased release of ACh from afferent fibers of the septal nuclei (Hasselmo and Giocomo, 2006). These high levels of ACh induce persistent spiking in pyramidal cells and support short-term potentiation and LTP, thus providing the hippocampus with favorable conditions for encoding new information while reducing interference from previously established patterns. It was suggested that under these conditions the cholinergic activity might contribute to hippocampal assembly formation (Hasselmo and Giocomo, 2006). On the other hand, during episodes of inactivity or slow-wave sleep, a reduction in ACh level releases existing connections from inhibition and enables transmission of established spatiotemporal patterns to the neocortex, thus supporting consolidation and recall of memories (Marrosu et al., 1995; Monmaur et al., 1997; Zylla et al., 2013). In fact, it was demonstrated that a disruption of such activity impairs spatial memory in rodents (Girardeau et al., 2009; Ego-Stengel and Wilson, 2010; Jadhav et al., 2012).

4.5. Induced neurogenesis and differentiation ACh can enhance LTP directly, by acting on pyramidal cells, and indirectly by acting on interneurons (Fig. 2). It was demonstrated that LTP could promote adult neurogenesis of granular cells

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within the DG (Bruel-Jungerman et al., 2006). A similar process was suggested for the developmental neurogenesis of PV-GABAergic interneurons in the striatum (Sadikot et al., 1998), and later it was demonstrated that generation of functional inhibitory interneurons does in fact occur in the DG of adult rats (Liu et al., 2003). Therefore, a plausible assumption might be that the increase of PV-GABAergic interneurons observed in the hippocampus of mdx is, at least partially, the result of an LTP-induced neurogenesis. Deng et al. (2009) studied neurogenesis in the DG in the adult mdx mouse. They have reported that a decreased production of NO from muscle, due to downregulation of neuronal NO-synthase associated with lack of dystrophin, caused a decrease in circulating NO, a signaling molecule known to promote differentiation of hippocampal neurons (Hindley et al., 1997). Though NO is considered to act locally due to its short half-life in circulation (Borland, 1991; Liu et al., 1998; Vaughn et al., 2000), some have reported that NO can be transported in its bioactive form for significant distances along the vascular bed (Rassaf et al., 2002). It was suggested that the reversible conversion of NO to S-nitroso-albumin enables NO to function as a systemic, regulatory molecule (Deng et al., 2009). In this regard, further investigations are needed to clarify the relationship between muscular NO and the effects on the CNS. In other studies it was reported that administration of NOsynthase inhibitors into adult mice resulted in an increased cell proliferation in neurogenic regions of the brain but decreased neuronal differentiation (Cheng et al., 2003; Packer et al., 2003; Moreno-Lopez et al., 2004). Consistent with these findings, Deng et al. (2009) reported increased proliferation of adult born cells with a concomitant reduction of differentiating new neurons in the DG of mdx mice exposed to a paradigm of voluntary running. It remains to be determined whether these alterations are already present at basal levels since sedentary mdx mice were not tested, and running is known to enhance adult neurogenesis in the DG (see, for review: Kempermann et al., 2010). Even though no information is provided about the stage of maturation of the newly born cells, immunonegative for mature neuron marker Neuronal Nuclei (Mullen et al., 1992), it is conceivable that the reported increase of cells is referring to newly born immature neurons, which in turn are known to possess a lower threshold for LTP induction (Schmidt-Hieber et al., 2004). It was suggested that exaggerated neuronal activity in the DG disrupts the functionality of the normal circuitry. The described alterations in cell proliferation and differentiation in the DG of adult mdx mice were restored by increasing the levels of NO in the serum (via over-expression of neuronal NO-synthase), suggesting a potential value of NO-based therapy for DMD treatment (Deng et al., 2009). Whether these alterations are consequential, i.e. decreased NO tone makes the cholinergic tone predominant thus favoring neurogenesis, or compensatory, i.e. an increase in ACh-mediated cell proliferation due to a decreased differentiation, is yet to be determined. Either way, both hypotheses could provide an explanation to the reported decrease in bioenergetics buffering capacity (Anderson et al., 2002) possibly reflecting the great increased, albeit transient, energetic demands associated with adult neurogenesis (Walton et al., 2012) and with increased synaptic activity during LTP (McEwen and Sapolsky, 1995). Therefore, increased neurogenesis could partially account for the increase of PV-GABAergic interneurons in mdx (Del Tongo et al., 2009), which in turn could cause an increase in mIPSCs. Additionally, it was shown that GABAergic input from PV+ neurons modulates survival of neurons (Ming and Song, 2011; Song et al., 2012, 2013), suggesting that this increase in mIPSCs might also have a role in sustaining the neurogenesis. Could such mechanism reflect a compensatory response to the NO-mediated decreased differentiation? Interestingly, greatest

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increase in PV-GABAergic neurons was demonstrated in the DG, which is consistent with the role of DG in filtering information to the subsequent network during the activated state of the hippocampus (Tsanov and Manahan-Vaughan, 2009) and could imply a function-related compensation. Moreover, recently it was shown that PV-interneurons affect the activation of neural stem-cell niche of the DG. Alterations of the GABAergic subpopulation seen in the mdx mice could therefore have an orchestrating role in adult neurogenesis (Song et al., 2012).

4.6. Overview of the suggested integrated model Are the above-mentioned alterations merely coincidental or are they oriented toward a recognizable goal? As stated earlier, there is an increase of ACh release during the formation of a hippocampal assembly, in which theta oscillations are superimposed by gamma oscillation, and a decrease in ACh release during consolidation. For such phenomenon to occur, precise input and synchrony must be present (Zylla et al., 2013). Moreover, it was shown that a unilateral injection of a nicotinic ACh receptor antagonist to CA1 prevents the increase in amplitude of mIPSCs during inhibitory avoidance task whereas, a bilateral injection blocks learning itself (Mitsushima et al., 2013). The authors discuss the role of ACh in balancing excitatory and inhibitory synaptic input onto CA1. Could the observed increase of mIPSCs in mdx reflect a mechanism aimed to maintain the correct functionality by preserving the formation of hippocampal assemblies? It was observed that perturbing network activity generated compensatory changes in synaptic strength that were in the right direction to restore average firing rates to baseline values, a phenomenon referred to as synaptic scaling (Turrigiano et al., 1998). Moreover, the homeostatic maintenance of neuronal excitability (Buzsáki et al., 2002), according to which there is a stable mean hippocampal output over time, and generation of persistent activity as a function of recurrent networks (Cossart et al., 2003), could provide a top-down explanation to the driving force behind the observed alterations suggesting a function-oriented compensation. Thus, instead of the classic approach of anatomic alterations causing functional deficits, there could be a bidirectional phenomenon in which the native functionality of a certain region dictates specific anatomic alterations aimed to preserve the network’s functionality. In the normally functioning brain, synchronized neuronal oscillations are a fundamental mechanism for enabling coordinated activity (Buzsáki and Draguhn, 2004; Fries, 2009). For such collective endeavor to occur timing must be precise. Timing of action potentials with millisecond precision depends on the presence of fast membrane potential fluctuations (Mainen and Sejnowski, 1995; Haider and McCormick, 2009) and such high-frequency patterns are often brought about by various endogenous oscillations (Buzsáki and Wang, 2012). We suggest that disruption of the normal oscillatory activity due to the reduced GABAA receptors interferes with cell synchronization, leading to adjustments in the excitatory/inhibitory ratio of the neuronal network aimed to restore the timing of neuronal activity and thus, normal oscillatory activity and cell synchrony. Such ongoing correctional pursuit is brought about by an increase of cells and an increase of activity that, in time, creates an increase in energetic demands that disrupts neuronal functionality in terms of network efficiency; this concept applied to the mdx mouse model is illustrated in Fig. 3 (the figure refers to the hippocampus, although some of the mechanisms described apply also to the cerebellum). Interestingly, neural oscillations are an energy-efficient mechanism for the coordination of distributed neural activity (Buzsáki and Draguhn, 2004); therefore, disruption of such activity could represent a contributing factor to the increased energetic demands.

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was uniform across layers II–VI; a more prominent expression was observed in the frontal cortex whereas the piriform and cingulate cortex demonstrated a distinct band beneath the molecular layer (Lidov et al., 1990, 1993). As in other areas, co-localization with GABAA receptors was also reported for the cortex (Knuesel et al., 1999; Brünig et al., 2002). 5.2. Alterations due to lack of dystrophin

Fig. 3. The alterations/compensations processes disrupting neuronal functionality in the mdx mouse. (1) Reduction in GABAA receptor number and clustering (Kueh et al., 2008, 2011; Knuesel et al., 1999) caused by reduced dystrophin expression. (2a) Increase in ACh (Rae et al., 2002) may be promoted by the reduction in GABAA receptors (Coccurello et al., 2002). (2b) Reduction in GABAA causes a perturbation to oscillatory activity (MacVicar and Tse, 1989; Buzsáki, 2002). (3a) Increase in ACh favors LTP induction (Burgard and Sarvey, 1990). (3b) Increase in ACh causes a perturbation in oscillatory activity (inferred from: MacVicar and Tse, 1989; Fisahn et al., 1998; Shimono et al., 2000). (4) Increased LTP (Vaillend et al., 2004) promotes proliferation and survival of adult generated neurons (Bruel-Jungerman et al., 2006). (5a) Decrease NO promotes cell proliferation (Cheng et al., 2003; Packer et al., 2003; Moreno-Lopez et al., 2004). (5b) Decreased NO causes a reduction in the differentiation of newly born cells (Hindley et al., 1997; Deng et al., 2009). (6) Increase in GABA PV+ neurons (Del Tongo et al., 2009) possibly due also to adult neurogenesis (Liu et al., 2003). (7) Newly generated immature neurons have a lower threshold for LTP induction (Schmidt-Hieber et al., 2004), thus causing an increase in LTP activity. (8a) The increase in GABA PV+ neurons leads to an enhanced inhibitory activity under the form of mIPSCs (Graciotti et al., 2008). (8b) GABAergic input from PV+ neurons modulates survival of neurons (Ming and Song, 2011; Song et al., 2012, 2013). (9) The increase in GABAergic activity provides a correction to the oscillatory perturbation (MacVicar and Tse, 1989; Buzsáki, 2002). (10) Transient synchronized oscillatory activity promotes LTP induction (Buzsáki et al., 2002). (11) LTP causes changes in intrinsic oscillatory dynamics (Narayanan and Johnston, 2007). (*) Hypothesized vicious cycle in which the increase in GABAergic activity necessitate further adjustments, thus causing a further increase in ACh. (**) Hypothesized driving force for correctional increase in GABAergic activity. Gray box: Over time, the perpetuating increased number of neurons, increased LTP, and enhanced inhibitory activity (i.e. mIPSCs), all contribute to raise the energetic demands, which in turn reduces the network efficiency (see text for further information).

Sbriccoli et al. (1995) were the first to report significant differences between brains of mdx mice and controls. Such differences included the absolute decrease in the number of corticospinal cells in mdx mice compared with controls. The cell packing density of cortical layer V neurons was higher in mdx than controls, while the cell packing density of corticospinal neurons was lower in mdx. Corticospinal cells constituted 50% of neurons present in layer V of controls, but only 35% in mdx, suggesting a selective damage to the corticospinal tract. The cross-sectional area of labeled neurons was 20% lower in mdx than controls; labeled cells also differed in shape with pyramidal cells being rounder in mdx. An investigation of spinal projecting brainstem neurons revealed a significant reduction of cells in the red nucleus and less marked reduction in the vestibular nuclear complex and medullary reticular formation and the raphe nuclei with the exception of the raphe pallidus nucleus (Carretta et al., 2001). The pattern of neurons that contain calcium-binding proteins in the cortex and brainstem in mdx was later investigated via immunoreactivity to PV, calbindin (CB), or calretinin. Findings included an increase in PV- and CB-containing cells in the sensorimotor cortex (Carretta et al., 2003), which were later analyzed using Voronoi diagrams, a method to study spatial relationships between cells. The latter analysis had revealed an increase in the number of polygons for both the PV- and CB-containing populations in the sensorimotor cortex, with PV-containing population being more numerous in V layer of the motor cortex and in the IV layer of the somatosensory cortex of mdx when compared with controls (Carretta et al., 2004). Alterations of the cortico-cortical network in sensorimotor areas were later examined demonstrating that while the ratio of infra- to supra-granular pyramidal cells remained the same, there was an absolute increase of pyramidal cells in mdx when compared with controls (Minciacchi et al., 2010). In the same study it was also reported that the basal dendrites of supra-granular pyramidal neurons had longer terminal branches yet a lower density of dendritic spines. In addition, the balance of associative projections from the supra- and the infra-granular cells remained unchanged yet there was an absolute increase in the number of associative neurons when compared in mdx when compared with controls. Biochemical alterations within the cerebral cortex of mdx included a decrease in the activity of the mitochondrial respiratory chain’s complex I in the prefrontal cortex and the cortex in general, and of complex IV in the prefrontal cortex; an increased activity of mitochondrial creatine kinase was shown in the prefrontal cortex and the cortex in general (Tuon et al., 2010). Oxygen consumption was significantly increased in cortical brain slices from the mdx mouse during pyruvate metabolism at low oxygen concentration (Rae et al., 2002).

5. Alterations and compensations in the cerebral cortex 5.3. Role of ACh in the cerebral cortex 5.1. Expression of dystrophin in the cerebral cortex Expression of dystrophin in the cerebral cortex principally occurs along the soma and dendrites of pyramidal cells and, though widely diffused, its distribution is not uniform (Lidov et al., 1990). This was demonstrated by measuring reactivity to dystrophin in different regions, many pyramidal cells in layers II and III of the parietal cortex were negative for dystrophin although distribution

Possible explanations for the alterations seen in the cerebral cortex do not differ much from those already suggested for the hippocampus and cerebellum. Though it was reported that there was no increase in choline containing compounds in the cortex, a decrease in AChE activity was reported in the brain of mdx mice (Comim et al., 2011); which could suggest that some increase in cholinergic activity, although not prominent, might also be present

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in the cortex. ACh was shown to enhance LTP in the cortex (Brocher et al., 1992; Hasselmo and Barkai, 1995) and was also described to be involved in processes of cortical neuroplasticity (Kuo et al., 2007). Furthermore, the role of ACh was documented in developmental stages of the cortex including progenitor cells proliferation and differentiation, neurogenesis, maturation and plasticity, and regulation of gene expression (Abreu-Villac¸a et al., 2011), which could account for the increase in PV-GABAergic and cortico-cortical pyramidal cells seen in mdx mice. 5.4. Network level correlates It was shown that down-regulation of PV at cortical GABA synapses reduces network gamma oscillatory activity (Sohal et al., 2009; Volman et al., 2011); conversely an increase in PV-GABAergic cells would be expected to increase gamma activity. The communication through coherence hypothesis (Fries, 2005) suggests that there are cycles of excitability in oscillatory networks; inputs will be most effective if they arrive at peaks of excitability. Thus, a mechanism that generates synchronous gamma oscillations in two regions might selectively route information from one region to the other. Considering the increase in PV-GABAergic cells and their effect on gamma oscillations, it might be possible to explain the increase in GABAergic cells as an attempt to reroute information back toward the network in a search for maintaining a specific oscillatory state. Moreover, it was suggested that early gamma oscillations represent a characteristic pattern of oscillatory activity in the somatosensory cortex of newborn rats (Gerasimova et al., 2014). Such activity was demonstrated to be most prominent in the cortical layer IV, where, in the mdx model, the PV-containing population was reported of being more numerous when compared with controls (Carretta et al., 2004). This could therefore represent an attempt to maintain a specific oscillatory state within the somatosensory cortex, at least at early stages of development, for the formation of thalamocortical somatosensory topographic maps (Gerasimova et al., 2014). The same argument can be made for the increase in corticocortical pyramidal cells, which might provide an explanation to the unaltered ratio of infra- to supra-granular pyramidal cells, when taking into account the aspect of attraction of information toward a certain area without altering the area’s functionality. Although, currently, there are no studies that measure the synaptic functionality within this context, it should be mentioned that some of these alterations could be due to altered input from the periphery. Indeed, it was shown that alterations in cortical excitability are produced by the subjects’ inactivity (Todd et al., 2006). Also, loss of sensory input has been shown to increase the intrinsic excitability of layer V pyramidal neurons in the cortex (Breton and Stuart, 2009). These findings could correlate with the clinical aspect of reduced mobility related to the muscular dystrophy (McDonald, 2002) leading to a decreased sensorial input and, in turn, increased intrinsic excitability. 6. Concluding remarks Conceptually, the scope of compensation is to counterbalance alterations that disrupt the natural course of processes. In biological systems, there are various mechanisms aimed to compensate disturbances for the maintenance of homeostasis. As with any dynamic system, such alterations and modifications are part of an ongoing process and are essential for the correct functionality of the system as a whole. We have reviewed a series of alterations occurring in the dystrophic brain and their possible compensatory responses. It is important to state that while the alterations reviewed might suggest adaptive or compensatory processes,

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we cannot exclude the possibility of such alterations being a direct consequence of the dysfunctional target gene. We propose a top-down explanation for such responses, according to which in order to preserve the network’s homeostasis, attempts are made to restore the timing of neuronal activity via adjustments to the network’s components. In this process we suggest that the ongoing, age-dependent modifications, in which the cholinergic tone potentially plays a central role, are those who eventually lead to disruption in the efficiency of neuronal networks, thus giving rise to cognitive impairments. Our model was based on knowledge derived from studies that focused mainly on the mdx mouse. The mdx mouse does not share all the behavioral and neurophysiological alterations with other mouse models of DMD, in particular when considering the mdx3cv and the Dp71-null mouse (Vaillend et al., 1998; Vaillend and Ungerer, 1999; Daoud et al., 2009). In light of these discrepancies, comparing the alterations/compensations processes in different animal models of DMD would be of value. Moreover, this model concerns the quota of DMD patients with cognitive impairments due to the absence of full-length dystrophin (i.e. Dp427), while the more severe cognitive defects of this disease (see above: Cognitive impairment in DMD.) may have no link to the model presented here. In line with our hypothesis, Beauparlant et al. (2013) recently proposed that compensatory mechanisms eventually lead to detrimental effects in a model of damaged nervous system. Interestingly, the possible involvement of cholinergic compensation was discussed in a study regarding Alzheimer’s disease and mild cognitive impairment (Dumas and Newhouse, 2011). It remains unclear whether the primary defect due to lack of dystrophin is a GABA or a cholinergic dysfunction. The cross-talk of the cholinergic/GABAergic systems is altered in many psychiatric disorders (as reviewed by Scarr et al., 2013). Therefore, in order to rule out possible primary defect of either one of these systems in the dystrophic brain, an approach integrating tissue- and temporalspecific genetic deletions of the components of each system would be instructive. Though treatments for DMD based on the modulation of utrophin were shown to alleviate DMD phenotypes in certain organs and tissues that coexpress dystrophins and utrophins in the same cells, improvement of cognitive functions using such methods did not prove to be beneficial with regards to the behavioral alterations in dystrophin-deficient mice and treatment for such alterations would likely require acting on specific dystrophindependent mechanisms (Perronnet et al., 2012). Attention has been directed toward the therapeutic potential of gene therapy for DMD. While advances have been made in the field (inducing dystrophin expression, preventing the downstream effects of muscle degeneration, and promoting muscle growth or replacement), there are still difficulties in bypassing immunological interferences namely those that accompany induced gene expression (Ferrer et al., 2004; Konieczny et al., 2013). In fact immune reactions to dystrophin during gene therapy trials have been reported to occur in some DMD patients (Leung and Wagner, 2013). Therefore, a better understanding of the natural history of this disease and the associated endogenously occurring alterations/compensations processes might provide fundamental knowledge for the development of more effective therapeutic approaches. Optogenetic technologies have been used to control the activity of distinct neuronal populations, including GABAergic and cholinergic cells (Sohal et al., 2009; Witten et al., 2010; Nagode et al., 2011), and light-sensitive nicotinic aceteylcholine receptors were recently generated (Tochitsky et al., 2012). The integration of such approaches in the mdx mouse could elucidate how a functional preference of a network might alter the CNS morphology in DMD. As for the cholinergic role in compensatory processes possibly

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Acetylcholine, GABA and neuronal networks: a working hypothesis for compensations in the dystrophic brain.

Duchenne muscular dystrophy (DMD), a genetic disease arising from a mutation in the dystrophin gene, is characterized by muscle failure and is often a...
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