The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia.

NIH Public Access Author Manuscript Curr Pharm Des. Author manuscript; available in PMC 2014 August 17.

NIH-PA Author Manuscript

Published in final edited form as: Curr Pharm Des. 2014 ; 20(31): 5069–5076.

The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia Kathryn M. Gill, PhD and Anthony A. Grace, PhD University of Pittsburgh, Pittsburgh, PA 15260, Departments of Neuroscience, Psychiatry and Psychology

Abstract


Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5 subunit of the GABAA receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity.

Introduction NIH-PA Author Manuscript

The efficacy of novel drug therapies in treating cognitive impairments in schizophrenia is remarkably low, and does not improve from the original, first generation antipsychotic drug treatments [1, 2]. As a core feature of schizophrenia, cognitive dysfunction typically precedes the onset of psychotic symptoms and is predictive of long-term prognosis. Most pharmacotherapies currently employed target the dopamine (DA) D2 receptor, consistent with dopamine system pathology observed in schizophrenia [3, 4]. However, there is compelling evidence that alteration in GABAergic system activity contributes to a dysfunctional dopamine system by interfering with the normal output of a key projection node, the ventral hippocampus (HPC). In addition, GABAergic interneurons are essential for the coordinated oscillatory activity across neural systems that occur during cognitive

Correspondence: K.M. Gill, University of Pittsburgh, Department of Neuroscience, A210 Langley Hall, Pittsburgh, PA 15260, USA, Tel: 1 412-624-7332, FAX: 1 412-624-9198, [email protected]. Financial Disclosures Competing financial interests. Johnson and Johnson, Lundbeck, Pfizer, GSK, Puretech Ventures, Merck, Takeda, Dainippon Sumitomo, Otsuka, Lilly, Roche, Asubio (A.A.G.). All other authors have no biomedical financial interests or potential conflicts of interest to report.

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performance. Consequently, novel pharmacotherapies for schizophrenia that target the GABA system are likely the best candidates for restoring cognitive function. Here we will review the link between diminished oscillatory activity and cognitive performance in schizophrenia. In particular, how specific alterations in the distribution of the various alpha subunits of the GABAA receptor observed in schizophrenia contribute to changes in oscillatory activity will be emphasized. Of great interest is the specific role of GABAA receptors that contain the α5 benzodiazepine-binding subunit (α5 GABAA receptors) in regulating the activity and mnemonic function of the vHPC. Finally, we will explore the evidence from animal models of schizophrenia the potential for promising novel GABAergic compounds.

Reductions in parvalbumin expression in schizophrenia is associated with alterations in normal network connectivity

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Oscillatory activity, or the coordinated activation of a large population of neurons within a structure or across brain regions, has several purported functions. For example, gamma oscillations (30–80 Hz) have been demonstrated to correlate with cognitive processes including perceptual binding, attention, arousal, and object recognition. Oscillations in the theta range (4–10Hz) serve complementary cognitive functions with gamma oscillations, in particular episodic memory formation. Both gamma and theta oscillations are observed independently in cortex and HPC [5–9]. However, gamma oscillations in both regions are modulated by, and embedded within, theta oscillations [8–11]. Oscillatory activity, in general, and gamma oscillations, in particular, are believed to represent the functional state and coordinated activity within neuronal systems [12]. Gamma oscillations are reported to correspond most closely to functional imaging studies of metabolic activation in brain regions, and as such are likely a better index of function than is neuronal firing [13]. Furthermore, coherence, or coordinated oscillatory activity between regions, is associated with functional interactions [14–16], and disruptions of rhythmic activity and coherence is associated with a pathological state such as that following drug abuse [17, 18] or lesions [9, 19, 20]. Therefore, normal oscillatory function is essential for optimal information processing and intellectual function, and these depend on GABAergic interneurons [21]. Thus, it has been suggested that the inhibitory input provided by different populations of GABAergic interneurons coordinate the timing of neuronal activity by synchronizing the firing of pyramidal neurons at different frequencies. Within the HPC and PFC, the fastspiking parvalbumin (PV)-expressing interneurons are considered responsible for the rapid IPSCs observed in pyramidal neurons and are vital for the generation of gamma oscillations. Computational models defining the mechanisms underlying the generation of gamma oscillations in HPC and PFC have defined a fundamental role for fast-spiking PV interneurons [21–23]. There is also corroborative experimental evidence that PV-expressing interneurons regulate gamma oscillatory activity. Selective ablation of NMDA receptors on PV-expressing interneurons in the HPC causes an increase in the power of gamma oscillations (35–85 Hz) in the CA1 area in addition to reduced theta phase-locking of gamma oscillations [24]. Paradoxically, genetic deletion of PV in mice causes an increase in gamma band power in the HPC putatively via a short-term enhancement of GABA release by fast-spiking interneurons that would normally express PV [25].

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The most consistently reported cellular alteration observed in the brain of schizophrenia patients is the reduction in the expression of the calcium-binding protein, PV [26–33] in GABAergic interneurons. Along with the reported reductions in the enzyme required for the decarboxylation of glutamate to GABA, GAD67, the alterations in PV expression bolster the proposal that abnormalities in inhibitory tone in schizophrenia contribute to the disturbances in oscillatory activity [34]. It is important to note that there are simultaneous reductions in PV, somatostatin (SST), and cholecystokinin (CCK) expression in both the PFC and HPC of schizophrenia patients, indicating the disruption of multiple interneuron populations [35, 36]. Recent advances with optogenetic techniques allows for the precise activation or inhibition of specific cell types in vivo. Consequently, the contribution of specific cell populations to oscillatory activity can be tested. Optogenetic stimulation of fast-spiking PVexpressing interneurons selectively enhances gamma oscillations [37, 38]. In corroboration, optogenetic inhibition of PV-expressing interneurons suppresses cortical gamma oscillations [38]. This would substantiate the relative importance of this population of interneurons in modulating oscillatory activity.


Animal models of schizophrenia provide results that are consistent with the loss of parvalbumin interneurons and evoked gamma activity observed in schizophrenia patients. It has been shown with the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia that PFC and HPC reductions in PV are associated with alterations in taskassociated oscillatory activity in both regions during performance of a latent inhibition task [39]. In an alternative animal model of schizophrenia, a neonatal lesion of the ventral HPC causes a reduction in both GAD67 and PV expression in entorhinal cortex, prefrontal cortex, and ventral HPC [40]. More compelling is the corresponding loss of oscillatory activity in both models. Consequently, there is a strong link between the PV reductions and the alterations in oscillatory activity observed in schizophrenia.


Therefore, specific classes of interneurons are necessary for the generation and synchronization of rhythmic activity in the brain, and loss of these interneurons in schizophrenia patients correlates with a loss of evoked gamma activity. Given that these rhythms are necessary for normal cognitive function, it is expected that the widespread disruption of the coordinated activation across brain regions in schizophrenia should also contribute to impaired cognition in patients. Working memory tasks require the coordinated activation of numerous brain regions, including PFC and HPC, for accurate performance. Specifically, in normal subjects there is an increase in gamma band oscillations that corresponds to increases in working memory load [41]. In contrast, there is a generalized increase in PFC gamma band power in schizophrenia patients under basal, resting, or neutral conditions that interferes with the dynamic modulation of gamma band activity during cognitive performance [42]. As a result, schizophrenia patients fail to demonstrate working memory load-associated increases in gamma activity in PFC [43]. Similar blunted gammaband synchrony in schizophrenia patients during performance of a task known to engage PFC networks has been reported [44].


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Changes in α subunits of GABAA receptors in schizophrenia identify NIH-PA Author Manuscript

potential therapeutic targets


There are several types of disorders which exhibit diminished cognitive capacity; primary among these is Alzheimer’s disease and schizophrenia. However, the origin of the cognitive deficits in these states is likely to be substantially different. In Alzheimer’s disease, a progressive loss of pyramidal projection neurons precedes and parallels the slow deterioration in cognitive function seen in this disorder, with the end result being massive cortical degeneration [45, 46]. In contrast, in schizophrenia cognitive decline begins slowly in the premorbid state, but then declines much more rapidly following the first psychotic break [47]. Moreover, cortical structural changes are much more subtle than those associated with Alzheimer’s at the deficit stage [48–50]. This suggests that unlike Alzheimer’s disease, which is a progressive neurodegenerative disorder, schizophrenia cognitive disruption may be due more to a disruption of cortical function. As a result, one would predict that the cognitive disruption of schizophrenia may be more readily “fixed” by restoring system function. This could be achieved by normalizing oscillatory activity via compensation for loss of selective interneuron types. Ionotropic γ-aminobutyric acid type A (GABAA) receptors, both synaptic and extrasynaptic, are primary targets of fast-spiking PV-expressing interneurons. GABAA receptors represent a heterogeneous population distinguished by their distinct subunit composition. GABAA receptors are pentameric heterodimers composed of a combination of various subtypes, α1–6, β1–3, γ1–3, δ, θ, ε, π and ρ1–3 [51, 52]. In addition, there is rich diversity in the regional and developmental patterns of distribution of the various GABAA subtypes that engender varied functional properties. Consequently, targeting a specific GABAA receptor subtype has vast therapeutic appeal for selectively modulating a particular function of GABAA receptors, such as cognitive enhancement, without unwanted side effects, e.g. sedation or muscle relaxation. The majority of GABAA receptors are distinguished for their sensitivity to benzodiazepines. Specifically, benzodiazepine-sensitive GABAA receptors contain the α subunits α1, α2, α3 or α5, a β subunit (mainly β2 or β3) and, in nearly all cases, the γ2 subunit in a 2:2:1 stoichiometry [51]. The α5 subunit primarily combines with the β3 and γ2 subunits on GABAA receptors. α1 GABAA receptors are present the most ubiquitously throughout the brain, with α2 GABAA receptors the second most prominent and concentrated in forebrain areas and the cerebellum [53]. The α5 containing GABAA receptors represent a small proportion of all GABAA receptors, less than 5 percent [54, 55]. However, α5 GABAA receptors have a restricted distribution within mainly limbic brain regions, including hippocampus, prefrontal cortex, and amygdala [56]. Within the hippocampus in particular, the relative expression of α5 GABAA receptor is much greater than the average expression in the entire brain by approximately 25% [57]. While exhibiting comparatively lower expression of α5 GABAA receptor than the hippocampus, layers V and VI of the cerebral cortex are additional regions with localized α5 GABAA receptor immunoreactivity [58]. Within the HPC, α5 GABAA receptors are located both extrasynaptically and on the dendritic spines of pyramidal neurons receiving input from GABAergic interneurons [58, 59]. In addition, in the intact hippocampus, α5 GABAA receptors are located on the dendrites of pyramidal neurons in the CA1 subregion [58]. The relatively confined distribution of α5 GABAA receptor suggests


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that targeting these receptors pharmacologically would selectively modulate hippocampal and cortical function and convey great therapeutic benefit in diseases such as schizophrenia.


In the cortex, pyramidal neurons containing GABAA receptors composed of different α subunits receive input from specific interneuron subpopulations. Post-mortem quantification of the mRNA for the α1, α2, α3, and α5 subtypes of the GABAA receptor in schizophrenia patients demonstrated lamina-specific alterations in the DLPFC [60]. There were significant reductions in α1 GABAA mRNA expression in layers 3 and 4, corresponding to input from PV-expressing basket cells. In addition, there was reduced α5 GABAA mRNA in layer 4 which receives GABAergic significant input from somatostatin SST-containing Martinotti cells. In contrast, α2 GABAA mRNA was elevated in layer 2 which receives GABAergic input from PV-expressing Chandelier neurons. Microarray and qPCR analysis have shown similar reductions in α5 GABAA mRNA, along with coincident reductions in GAD67, in the DLPFC of schizophrenia patients [61]. In conclusion, the inhibitory drive from multiple interneuron populations in PFC is likely destabilized in schizophrenia and selective manipulation of the specific α subunits of the GABAA receptor could have subtle and unique effects on PFC oscillatory activity generated by pyramidal neurons.


Alterations in α5 GABAA receptor binding in the HPC of schizophrenia patients have also been reported. PET scans of [11C]Ro15-4513, a GABAA/benzodiazepine compound with high affinity for the binding α5 GABAA receptor, in schizophrenia patients revealed a negative correlation between negative symptom severity and α5 GABAA binding in PFC and HPC [62]. Negative symptoms represent a loss in affective state in schizophrenia patients, and as is the case for cognitive impairments, antipsychotic drugs fail to adequately treat these symptoms. In sum, in addition to changes in PV-expression by GABAergic interneurons, there is evidence for simultaneous changes in post-synaptic GABAA receptor expression in the PFC and HPC of patients with schizophrenia.

α5 GABAa receptor activity as potential regulator of PFC and HPC oscillatory activity


A proposed function of α5 GABAA receptors in the hippocampus is the tonic regulation of inhibitory inputs to pyramidal neurons. Of particular interest is the involvement of the α5 GABAA receptor present on pyramidal neurons in the regulation of GABA inputs arising from PV-expressing interneurons. There are three types of PV-expressing neurons in the hippocampus, basket cells, axo-axonic cells, and bistratified cells. PV interneurons have synaptic contacts with pyramidal and granule cells occurring mainly at the somata, axon initial segments, and proximal dendrites [50–52]. There is overlap in the expression of PV and α5 GABAA receptor in the pyramidal cell layer of CA1 and the granule cell layer of the dentate [37]. Since PV will chelate calcium quickly due to its high affinity [63, 64], neurons with high PV expression have a more brief after hyperpolarization and hence can sustain high frequencies of firing [65–67]. This is consistent with the involvement of PV-containing interneurons in gamma rhythm generation. By virtue of their location at GABAergic synapses onto pyramidal neurons in HPC and PFC, α5 GABAA receptors are positioned to participate in the regulation of oscillatory activity.


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Interference of GABAA receptor activity by administration of bicuculline can reduce gamma oscillations in both HPC and PFC in vitro [68–70]. It has been suggested that there are two kinetic classes, fast and slow, of GABAA inhibitory postsynaptic currents (IPSC) onto CA1 pyramidal neurons [71, 72]. The kinetics of the different alpha subunits imbues them with different modulatory capabilities of oscillatory activity through their generation of either GABAA, fast or GABAA, slow IPSCs. Figure 1 illustrates the converging GABAergic input onto HPC pyramidal neurons from diverse interneuron populations. The GABAA, fast IPSC observed in pyramidal neurons is rapidly activated and rapidly decayed. GABAA, fast IPSCs are mediated by proximal and dendritic synapses, likely from basket and chandelier cell projections to α1 and α2 GABAA postsynaptic receptors, respectively [73]. In contrast, GABAA, slow IPSCs demonstrate slow rising and slow decaying potentials mediated by dendritic synapses containing α5 GABAA receptors [74] [75].


In vitro recordings in HPC slices have shown that activation of GABAA, slow interneurons can suppress the influence of the GABAA, fast network, both by attenuating the rate of GABAA, fast IPSCs in CA1 pyramidal neurons as wells as direct inhibition of GABAA, fast basket and chandelier interneurons [74]. Interestingly, the GABAA, slow suppression of the GABAA, fast network occurs with a time constant in the range of the theta frequency, (125– 400 ms). Therefore, GABAA, slow interneurons, acting at the α5 GABAA postsynaptic receptors can contribute to the theta frequency modulation of gamma rhythms. The tonic inhibition provided by α5-containing GABAA receptors is likely important for coordinating spike timing of pyramidal neurons and balancing excitation [75, 76]. Genetic deletion of α5GABAA receptor blocks tonic inhibitory currents recorded from pyramidal neurons in the CA1 region of HPC slices [77, 78]. Moreover, pyramidal neurons from α5 −/ − mice exhibit reduced depolarizing current thresholds for action potential generation in comparison to wild-type controls [78]. In addition, α5GABAA receptors are also important for regulating gamma oscillatory activity in HPC slice preparations [75, 79, 80]. Genetic reduction of α5GABAA receptor expression can increase the occurrence of spontaneous gamma in the CA3 pyramidal layer [75], as well as the power of kainite-induced frequency oscillations [79]. Thus, it appears that α5GABAA receptor act to limit increases in gamma power.


An important distinction is that between spontaneous and evoked gamma power. The data on baseline, spontaneous gamma power in schizophrenia is unclear, with more publications suggesting an increase in baseline gamma [81–84]. This is also observed with administration of psychotomimetic drugs such as ketamine [85–87]. On the other hand, the literature is fairly consistent on an attenuation of stimulus-evoked gamma rhythms both in schizophrenia [88–92] and in animal models of schizophrenia [39]. The diminished evoked gamma is proposed to be more relevant, since it would correlate with decreased metabolic responses to evoking stimuli [93] and hence the diminished accuracy in processing of sensory information. Therefore, with a decrease in parvalbumin interneuron-mediated evoked gamma activity, the schizophrenia patient, as well as animal models showing similar disruptions in parvalbumin [39], would show diminished capacity to accurately respond to relevant stimuli.


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Role of α5 GABAA receptor in Cognitive Function NIH-PA Author Manuscript NIH-PA Author Manuscript

Inherent to their rich expression in the HPC and PFC, α5 GABAA receptors are involved in various cognitive processes. Studies in rodents have confirmed the participation of α5 GABAA receptor in cognition. As described earlier, there are electrophysiological consequences observed in the HPC following genetic manipulation of the α5 GABAA receptor in mice. Such mutations have shown mixed results in the performance of tasks requiring an intact HPC. Mice with reduced expression of α5-containing GABAA receptors, either as a result of deleting the α5 subunit or as a consequence of introducing an α5H105R point mutation [94, 95] have enhanced cognitive performance during spatial learning of a water maze task as well as trace fear conditioning. In contrast, other studies involving genetic reduction of α5 GABAA receptors have shown altered memory for the location of objects as well as contextual fear conditioning, while sparing other types of learning that does not require an intact HPC, such as stimulus response behaviors [96, 97]. This would suggest a subtle alteration in normal HPC mnemonic function following the loss of α5 GABAA receptors during development. Indeed, the ability of α5 GABAA receptors to alter HPC and PFC activity imparts the significance of this GABAA receptor subtype in schizophrenia, a disorder with known HPC and PFC pathology. As such, antagonism or genetic deletion of α5GABAA receptor has behavioral consequences that resemble some of the behavioral abnormalities seen in schizophrenia, including reduced prepulse inhibition to startle [98] and impaired latent inhibition [99]. Consequently, with otherwise normal HPC activity, loss of the α5 subunit has behavioral consequences in the processing of contextual stimuli.


Pharmacological manipulations of α5 GABAA receptors in intact animals have reinforced the importance of input from this GABAergic subpopulation of interneurons in mediating HPC-dependent cognitive behaviors. There are a variety of α5 selective compounds that promote cognitive improvements. Memory impairments during a word recall task that were observed following alcohol ingestion can be ameliorated by a α5 GABAA receptor inverse agonist, Ro15-4513, also known as a negative allosteric modulator [100]. A similar compound, RO4938581, also a α5 GABAA receptor inverse agonist, has also demonstrated cognitive-enhancing properties in rodents. When administered alone, RO4938581 has no impact on performance of either a delayed match-to-position task or the Morris water maze [101]. However, RO4938581can reverse a scopolamine-induced impairment during the delayed match-to-position task. Similarly, a diazepam-induced reduction in spatial learning is blocked by RO4938581 treatment. It is important to note that pharmacological reductions in α5 GABAA receptor typically have no effect on their own, but they are effective in ameliorating disruptions in normal cognitive performance in intact animals. Given the data showing that disruption of alpha 5 GABAA receptors can impair cognition, and that antagonism of this receptor can reverse cognitive disruptions due to other mechanisms suggests that the multiple GABAA α5 targets exist in a delicate balance within the interneuron-pyramidal neuron network in the hippocampus. Thus, disruption in either direction can have potent impacts on the induction or the alleviation of cognitive disturbances.


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α5 GABAA receptor positive allosteric modulators: Promising novel NIH-PA Author Manuscript

therapeutics


The MAM model of schizophrenia recapitulates the behavioral and neurophysiological symptoms of schizophrenia. Pregnant dams are treated with MAM on gestational day 17, a critical time point for HPC and PFC development [102]. MAM-treated offspring exhibit behavioral-abnormalities consistent with schizophrenia, including increased behavioral responses to amphetamine, impairments in pre-pulse inhibition, latent inhibition, spatial working memory with extended delay, and extradimensional set-shifting [103–107]. As indicated earlier, MAM rats also demonstrate reductions in PV-expression in PFC and vHPC along with corresponding alterations in task-associated gamma oscillations [39]. The vHPC has been identified as a site of pathology in the MAM model, given the loss of PV interneurons in this structure and the corresponding disruption of sensory evoked gamma activity and shifts in baseline local field potential power in specific frequency bands [39, 108]. Furthermore, hyperactivity in the vHPC appears to underlie the dopamine system hyperresponsivity observed in the MAM rat (Figure 2); since inactivation of this region with TTX restores normal DA neuron activity levels and reverses the heightened behavioral response to psychostimulants [108]. This is consistent with studies showing increases in hippocampal activity in schizophrenia that correlate with psychosis [109–111], and increased glutamate utilization in hippocampal-striatal pathways that correspond to increased dopamine system fluorodopa uptake [112, 113]. Consequently, a compound that selectively reduces vHPC output could potentially restore normal dopaminergic tone, vHPCPFC oscillatory activity, and ultimately cognitive performance in MAM animals.


SH-053-2′F-R-CH3 (α5GABAA receptor positive allosteric modulator, PAM) is a novel, commercially unavailable compound unique for its selectivity for the α5 subunit of the GABAA receptor [114, 115]. As described previously, the relatively confined distribution of α5 GABAA receptors mainly in the vHPC makes compounds selective for these receptors especially amenable for more precisely regulating vHPC activity (Figure 2). Indeed, when administered systemically or directly infused into the vHPC, there is a reduction in both the hyperactivity of the dopamine system, as well as the locomotor response to amphetamine, in MAM rats following α5GABAA PAM treatment [116] without affecting the state of this system in normal rats. Electrophysiological recordings from the vHPC, confirmed that the α5 GABAA PAM can reduce the excitatory responses of vHPC neurons to entorhinal cortex stimulation. Potentially, this could reflect a means by which hippocampal responses to potentially irrelevant sensory stimuli conveyed from entorhinal cortex are blunted. A similar α5-targeting compound has also demonstrated therapeutic potential in an alternative animal model of schizophrenia. The reeler mouse model involving a 50% downregulation of reelin expression (mRNA and protein) reproduces the dendritic spine and GABAergic deficiencies described in schizophrenia. Mice heterozygous for this mutation display schizophrenia-like sensorimotor deficits that are reversed by treatment with imidazenil, a compound with relatively high selectivity for α5 GABAA receptors [117, 118]. Normalizing hippocampal activity could have widespread actions within systems believed to be disrupted in schizophrenia. The above data suggest that this hyperactive ventral HPC Curr Pharm Des. Author manuscript; available in PMC 2014 August 17.

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underlies the dopamine hyper-responsivity that is thought to be the basis of psychosis. Moreover, the limbic hippocampal region projects to the prefrontal cortex, where it can influence cognitive processing via alterations in theta-modulated gamma activity. This region also projects to the cingulate cortex and amygdala; areas involved in emotional regulation that may contribute to the negative symptoms of schizophrenia. Therefore, a disruption of hippocampal rhythmicity and the resultant hyperactivity has the potential to disrupt regulation across a widely distributed circuit. Normalization of activity within this circuit could therefore provide an effective therapeutic avenue for treating a broad range of schizophrenia symptoms including psychosis.

Conclusion Disruption of inhibitory activity in schizophrenia causes widespread disturbance of the coordinated activation across brain regions required for normal cognitive function. Consequently, a positive allosteric modulator of α5 GABAARs could potentially compensate for pathological decreases in PV-expressing interneuron functionality. The successful treatment of cognitive dysfunction in schizophrenia has major implications for improving both the occupational viability and quality of life of patients.


Acknowledgments This work was supported by United States Public Health Service Grant MH57440 (A.A.G.)

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Figure 1.


HPC pyramidal (PYR) neurons receive GABAergic input from a diverse population of interneuron cell types that are implicated in the HPC dysfunction observed in schizophrenia patients. In this highly simplified diagram, basket cells expressing the proteins parvalbumin (PV) and cholecystokinin (CCK), both significantly reduced in schizophrenia patients, preferentially synapse onto α1 and α2 expressing regions, respectively, of the proximal dendrites and soma of the PYR. Both α1 and α2 GABAA receptors mediate fast GABAergic conductances important for gamma oscillations. In contrast, interneurons expressing somatostatin (SST), also reduced in schizophrenia patients, in the stratum lacunosummoleculare layer synapse onto both the distal dendrites of PYR neurons as well as neighboring basket cells. SST interneurons likely target α5 GABAA receptors and generate slow GABAergic conductances in both PYR neurons and interneurons. α5 GABAA receptors also modulate gamma and theta oscillatory activity in the HPC. α5 GABAA binding is also significantly reduced in the HPC of schizophrenia patients. Consequently, there are widespread alterations within HPC interneuron networks in schizophrenia that contribute to HPC hyperactivity and disruptions in normal oscillatory activity.


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Figure 2.

(A) In the MAM neurodevelopmental model of schizophrenia, aberrant activity in the ventral HPC increases tonic dopamine neuron activity in the ventral tegmental area (VTA) via a polysynaptic projection. Consequently, the ventral HPC excites neurons in the nucleus accumbens (NAc) that, in turn, inhibit ventral pallidal (VP) activity. Given that the VP tonically inhibits dopamine neurons of the VTA, abnormal increases in glutamatergic output of the ventral HPC results in an increase dopamine neuron activity in MAM rats. (B) By selectively targeting α5 GABAA receptors in the ventral HPC, treatment with the novel a5 GABA A receptor positive allosteric modulator (PAM), SH-053-2′F-R-CH3, will reduce the pathological increase in ventral HPC activity. Consequently, reductions in dopamine system activation are an indirect result of the altered ventral HPC output. Adapted from [119]

NIH-PA Author Manuscript Curr Pharm Des. Author manuscript; available in PMC 2014 August 17.

Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits.

Remediation of cognitive deficits in schizophrenia.

The early longitudinal course of cognitive deficits in schizophrenia.

[Improvement of cognitive deficits in the focus of new treatment strategies in schizophrenia].

Potential Role of Oestrogen Modulation in the Treatment of Neurocognitive Deficits in Schizophrenia.

The Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Type 2 Diabetes.

Potential Role of Thyroid Receptor β Agonists in the Treatment of Hyperlipidemia.

GABAA receptor modulation of memory: the role of endogenous benzodiazepines.

Amusia and cognitive deficits in schizophrenia: is there a relationship?

The prefrontal cortex in schizophrenia and other neuropsychiatric diseases: in vivo physiological correlates of cognitive deficits.

Cognitive mapping deficits in schizophrenia: a critical overview.

Motivational deficits and cognitive test performance in schizophrenia.

Failures of cognitive control or attention? The case of stop-signal deficits in schizophrenia.

Factors affecting cognitive remediation response in schizophrenia: the role of COMT gene and antipsychotic treatment.

The discovery of diazepinone-based 5-HT3 receptor partial agonists.

The future of 5-HT1A receptor agonists. (Aryl-piperazine derivatives).

Developing treatments for cognitive deficits in schizophrenia: the challenge of translation.

Self-rated and performance-based empathy in schizophrenia: the impact of cognitive deficits.

Developmental lag and course of cognitive deficits from the premorbid to postonset period in schizophrenia.

Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia.

The Role of Metabotropic Glutamate Receptor Genes in Schizophrenia.

The role of memory in awareness of memory deficits in Alzheimer's disease, schizophrenia, and brain injury.

Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease.

In search of potent 5-HT6 receptor inverse agonists.