(1990) Proc. Natl Acad. 5ci. USA 87, 6349-6352 29 Schroder, G. D. (1979) Ecology 60, 657-665 30 Jacobs, L. F. (1992) Anim. Behav. 43, 585-593 31 Behrends, P., Daly, M. and Wilson, M. I. (1986) Behaviour 96, 210-226 32 Randall, J. A. (1991) 8ehav. Ecol. Sociobiol. 28, 215~/1220 33 Jacobs, L. F. and Spencer, W. (1991) Soc. Neurosci. Abstr. 21, 134 34 Jerison, H. J. (1973) Evolution of the Brain and Intelligence, Academic Press 35 West, M. J. and Schwerdtfeger, W. K. (1985) Brain Behav. Evol. 27, 93-105

36 Schwerdtfeger, W. K. (1984) Structure and Fiber Connections of the Hippocampus, Springer 37 Harvey, P. H. and Krebs, J. R. (1990) Science 249, 140-146 38 Bennett, E. L., Diamond, M. C., Krech, D. and Rosenzwieg, M. R. (1964) Science 146, 610-619 39 Turner, A. M. and Greenough, W. T. (1985) Brain Res. 329, 195--205 40 Black,J. E., Zelazny, A. M. and Greenough, W. T. (1991) Exp. Neurol. 111,204-209 41 Lipp, H-P. eta/. (1989) Experientia 45, 845-859 42 Schwegler, H., Crusio, W. E., Lipp, H-P. and HeimrJch, B. (1988) Behav. Genet. 18, 153-165

Caldum-bin@ngproteinsin the nervoussystem K. G. B a i m b r i d g e , M . R. Cello a n d J. H. Rogers

Among the many calcium-binding proteins in the cesses 6-8. Although the function of these CaBPs in KennethG. nervous system, parvalbumin, calbindin-D28K and neurons is unknown, antibodies against these proteins Baimbridgeis at the calretinin are particularly striking in their abundance have been employed as neuroanatomicai markers 8-13. PhysiologyOept, and in the specificity of their distribution. They can be The CaBPs have an advantage over other neuronal Universityof British found in different subsets of neurons in many brain markers in that, by virtue of their high solubility, they Columbia,2146 regions. Although it is not yet known whether they play a are usually present throughout the cytosol, even in HealthSciencesMall, 'triggering~ role like calmodulin, or merely act as buffers the thin processes of neurons, therefore facilitating Vancouver,BC to modulate cytosolic calcium transients, they are studies of neuronal shape and connectivity. In gen- CanadaVbT 1W5, Marco R. Cellois at valuable markers of neuronal subpopulations for ana- eral, different CaBPs are segregated to separate the Instituteof tomical and developmental studies. subpopulations of complementary systems in the Histolo~/and brain, but there are many cases of cells harbouring GeneralEmbryology, Calcium ions (Ca 2+) play a key role in transmembrane two or more types of CaBP; for example, Purkinje Universit~tP~rolles, signalling and the intracellular transmission of signals. cells8 and many neurons within the spinal cord 14'15 CH-1700Ftibourg, However, Ca2+ does not act alone. Many cells contain contain both parvalbumin and calbindin-D28K. Switzerland,and a variety of cytosolic calcium-binding proteins However, some nerve cells, including most pyramidal John H. Rogersis at (CaBPs) which either modulate or mediate the actions cells of the cerebral cortex and hippocampus 16'~7, do the Physiological of this ion*. The more notable of these are listed in not contain any of the known members of the EF-hand Laboratory, Box 1 and include several ubiquitous proteins that family of CaBPs, with the exception, perhaps, of Universityof Cambridge, mediate biochemical responses to intracellular Ca2+ calmodulin. Cambridge, signals. In this review, however, we will concentrate Antibodies to CaBPs have been used to follow the UK CB23EG. on the CaBPs that have more restricted distributions ontogeny of various functional systems 18-21. In adin neurons, and are abundant but of unknown function: dition, they have aided the elucidation of highly parvalbumin, calbindin-D28K and calretinin. These proteins are members of the 'EF-hand' famBox 1. Major calcium-binding proteins in the nervous system ily of CaBPs (Ref. 2), which is defined by an amino acid sequence similar to the consensus sequence shown Present in most cell types, Present in certain cell types in in Fig. 1A. This sequence folds up into a helix-loopincluding neurons CN5 helix pattern, known as the EF hand, in which hydrophilic sidechains bind one calcium atom (Fig. 1B). EF-hand family EF-hand family For didactic purposes, two groups of EF-hand CaBPs Calmodulin Parvalbumin are defined, the 'trigger' and the 'buffer' pro(ubiquitous calcium-dependent (in some neurons) teins 3. Trigger proteins (calmodulin and troponin-C) modulator of protein kinases change their conformation after binding Ca2+, and Calbindin-D28K and other enzymes) (in some neurons) can then modulate the activity of various enzymes 4 Calpains and ion channels 5. The buffer CaBPs, such as Calretinin (calcium-dependent proteases) parvalbumin in muscle or the 9-kDa calbindin in the (in some neurons) mammalian gut enterocyte, are believed to make up a e~-Actinin Recoverin, visinin more passive system, which may limit a stimulated (in photoreceptors; regulate Other families rise in intracellular free calcium concentration. The guanylyl cyclase) 28-kDa calbindin (calbindin-D28K) replaces the Annexins S100~,13 smaller form in the chick gut enterocyte; it is only this (Ca2+-phospholipid-binding (in glia; effects on larger form that is found in neurons of the central and proteins; of unknown function, phosphorylation and neurite peripheral nervous systems, including the enteric but implicated in exocytosis) outgrowth) nervous system, of birds, mammals and other Protein kinase C species. Gelsolin Parvalbumin, calretinin and calbindin-D28K occur in (and other cytoskeletondistinct subpopulations of neurons that may therefore associated proteins) be distinguished by specific calcium-dependent proTINS, Vol. 15, No. 8, 1992

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A

EO-

"OO AF

•

~ ...... I

• O~KDGD~' F N N x

y

z

-y

-x

E_F • • O ~ L -z

Fig. 1. (A) Consensus amino acid sequence for the 'El: hand' domain; second row of letters indicates alternative amino acids; N-terminal on left (from Ref. 1). The single-letter amino acid code is used; 0 can be I, L, V or M, and a dot indicates a position with no strongly preferred residue. Each residue listed is present in more than 25% of sequences, and those underlined are present in more than 80% of sequences. (B) Three-dimensional, helix-loophelix conformation of the EF hand (from Ref. 2). The hydrophilic side chains of the loop residues (x, y, z, -x, -y, -z), shown in (A), bind one calcium ion.

specific connectivities between inputs and target cells identifiable on the basis of their immunoreactivity for CaBPs. This technique was elegantly used in the demonstrations of large-calibre afferent inputs from the dorsal raph6 serotonergic neurons to interneurons containing calbindinD28K in the hippocampal formarion22 and cerebral cortex23, and in the identification of a GABAergic disinhibitory septohippocampal projection to the dendrites of interneurons identified on the basis of calbindin-D28K or parvalbumin immunoreactivity24.

Examples of distributional patterns of calcium-binding proteins The most complete mapping of the brain for parvalbumin, calbindinD28K and calretinin has been done in the rat 8-13. The three proteins are detected in different sets of neurons with only partial overlap. The CaBP distributions in the retina and in the cerebral cortex are described below. Retina. Fortunately some aspects of the distribution of CaBPs in the retina are conserved in different vertebrates2s-27. A single CaBP, calbindinD28K, may be found in different types of cells ranging from cones (which show graded hyperpolarization in response to light) to ganglion cells (which fire typical action potentials). Horizontal cells always contain abundant CaBPs, but the protein varies in different species. For example, horizontal cels contain calretinln in chicks, calbindin in rats, and both of these plus parvalbumin in cats 2s. These patterns suggest that cones may specifically require caibindin for some function, whereas horizontal cells merely require plenty of CaZ+-binding capacity no matter what the protein is. Antibodies against these three CaBPs also allow one to identify numerous subtypes of amacrine and ganglion cells. Two images of cat retina stained for calbindin-D28K and calretinin are shown in Figs 2 and 3. The retina also contains several unique CaBPs. One of these, called recoverin, is the only one found in rods, and is a recently discovered 'trigger protein', which mediates adaptation to light by activating guanylyl cyclase28 ' 29 . In contrast to calmodulin, recoverin is active in the calcium-depleted state and is inactive in conditions of high calcium concentration. A similar protein, visinin3°, is present in avian cones. However, the major Ca2+-buffering capacity in photoreceptors is provided by arrestin, an abundant protein Fig. 2. Cat retina stained for calbindin-D28K (red) and calretinin (green); transverse section. Cones (top) contain calbindin-D28K only; horizontal cells (the yellow band across the middle) contain both calbindin-D28K and calretinin; and many amacrine cells (in lower half) contain one orboth proteins. (All figures are by J. H. Rogers using calbindin-D28K antiserum from D. E. M. Lawson. This i m a g e was taken from a confocal laser scanning microscope by courtesy of P. McNaughton; see Ref. 25.)

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Fig. 4. Local-circuitneurons in the rat cerebral cortexstainedfor ca/bindin-D28K (green)and ca/retinin (red)(see Ref. 32). (Calbindin-D28K antiserumcourtesyof D. E.M, Lawson.)

involved in termination of the light-induced signal31; its Ca2+ binding may be merely incidental. Cerebral cortex. In the cerebral cortex, CaBPs are prominent only in small numbers of neurons (Fig. 4), which are non-pyramidal cells containing GABA and/ or peptide neuromodulators. (However, many other cells in layers II and III stain weakly for calbindin.) There is no overlap between cell types that stain positively for calbindin-D28K and those that stain for calretinin, and only limited overlap of either type of cell with the parvalbumin-positive ceils. Antibodies to CaBPs are excellent markers for known types of neuronal cell: parvalbumin occurs in chandelier33'34 and basket ceUs33-35; calbindin-D28K is found in double-bouquet cells36; and calretinin occurs in bipolar and bitufted cells 13. However, not all

none do so in the rat 44. These few examples of differences in protein distribution between species urge caution in making generalizations about the occurrence and possible function of CaBPs. Nevertheless, there is a striking similarity in the distribution of most stained cell types from the cerebral cortex, hippocampus, striato-nigral system and cerebellum in rodents, monkeys and humans.

Calcium-binding proteins and neurotransmitters A distinctive feature of many cortical neurons expressing CaBPs is that they represent subpopulations of GABAergic cells. Parvalbumin is colocalized with GABA in cerebral cortex4~49, dorsal lateral geniculate nucleus5°, hippocampus 51-s4 and cerebellum. Calbindin-D28K is also co-localized with GABA in some cells s, as is calretinin 32. Interestingly, these three CaBPs occur in almost entirely separate Fig. 3. Cat retina stained for calbindin-D28K (red) and calretinin (green); oblique section. At the top are horizon- populations of GABAergic cells in the cortex and tal cells; below are the amacrine cells, showings mosaic of double-positive (brown) cells with fewer cells positive for calbindin-D28K or calretinin alone (see Ref. 25). (Calbindin-D28K antiserum courtesy of D. E. M. Lawson.)

ceils of one class express the same protein; for example, double-bouquet cells may be positive for calbindin-D-28K or tachykinin37, while chandelier neurons may stain positive for parvalbumin or corticotropin releasing factor38. Therefore, immunoreactivity to CaBPs cannot be used to count the total number of cells of a given neuronal type, but it does indicate a previously unappreciated diversity among the non-pyramidal cells. Similar results are found in other forebrain regions, such as the hippocampus and the olfactory bulb (Fig. 5).

Fig. 5. Ratolfactorybulb stainedfor ca/bindinD28K(red)and calrebhin(green), showing one g/omeru/us. Thetwo proteins/abe/ separatepopu/atJons of pefis/omeru/ar ceils, whichare/oca/ inhibitorycells. (Ealbindin-D28K antiserumcourtesyof D. E. M. Lawson.)

Calcium-binding proteins in different species It is becoming quite clear that the distribution of CaBPs is not invariant in different species. For example, the perforant path contains parvalbumin in only gerbils and not in other species39, and CA1 pyramidal neurons contain calbindin-D28K in rats, but not in humans, rabbits or guinea pigs 8'1°'4°'41. Many thalamic nuclei express calbindin-D28K and parvalbumin in monkeys42 but not in rats 8, and almost all cholinergic neurons in the nucleus basalis of Meynert of the monkey express calbindin-D28K 43'44, whereas TINS, Vol. 15, No. 8, 1992

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other forebrain regions, whereas calbindin-D28K and parvalbumin are almost always co-localized in nonGABAergic neurons in the rat spinal cord 14'15 and dorsal root ganglia 55'56. In the cerebral cortex and hippocampus, CaBPs are detected in some, but not all, neurons containing peptide neuromodulators. Calretinin coexists with vasoactive intestinal peptide in some cells32, and calbindin-D28K coexists with somatostatin in some cells32'57, whereas parvalbumin is not found in any neurons containing somatostatin, cholecystokinin 46 or corticotropin-releasing factor38. Thus, antibodies to CaBPs seem to detect a large population of GABAergic, but non-peptiderglc, neurons, of which the basket cell is a major representative. Since L~rvalbAmin coexists with giycine in reticular neurons ~, and with glutamate in spiral ganglion cellss9, it seems most likely that the expression of a given CaBP is not determined by a neuron's neurotran~smitter content, but instead by key physiological properties of the'cell. Indeed, a strong correlation has been demonstrated between the occurrence of parvalbumin and the fast firing properties of hippocampal interneurons 52. In accordance with their fast firing rate, parvalbumin-containing neurons have, in general, a high metabolic rate, reflected by a high cytochrome oxidase activity, detected at the systemic 60'61 and the cellular levels55'62

Calcium-binding proteins and neuronal excitability Unlike parvalbumin, calbindin-D28K and calretinin show no obvious correlation with the properties of the neurons that contain them. Each protein is present in a wide variety of neurons: excitatory and inhibitory, fast-responding and slow-responding, long-range and short-range. The distribution patterns suggest that these CaBPs are not essential for the basic properties of neurons, but that they may modulate the properties of particular subtypes of cells. One of the first hypotheses concerning the roles of calbindin-D28K 1°,63 and parvalbumin 45 suggested that a link existed between their expression and the excitability of nerve cells. These two CaBPs bind Ca2+ with high affinity (Kd is sub-micromolar) and are found in high concentrations; thus, by virtue of their Ca2+-buffering capacities, these proteins potentially have a number of different effects on the cell. These effects could include: altering the duration of action potentials; promoting neuronal 'bursting' activity (by inhibiting the Ca2+-dependent K + current); allowing for a greater contribution of Ca2+ entry to the overall membrane depolarization (by inhibiting CaZ+-dependent inactivation of voltage-operated Ca 2+ channels); and protecting cells against the damaging effects of excessive calcium influx during prolonged periods of high activity. The magnitude of such effects cannot be predicted without knowing the exact time-course of calcium binding by the proteins in vivo, their local distribution beneath the cell membrane, and the relative abundance of different channel subtypes in particular neurons 64. At high concentrations of CaBPs and Ca2+, local regions of saturating Ca2÷ concentrations might be 'walled in' around individual channels. At lower concentrations of CaBPs, the main effect of these proteins might be to slow down the Ca 2+ transients. 306

Of the proteins described, parvalbumin is the most likely to act merely as a calcium-binding agent, and this is believed to be its role in skeletal muscle. It binds Ca2+ slowly (because of competition by Mg2+, which takes up to 1 s to exchange for Ca2+), and it has a less conserved amino acid sequence than either calbindin-D28K or calretinin 65. Cells transfected in vitro with parvalbumin cDNA show a decreased mitotic rate 66 and increased motility (Andreessen, C., Gotzos, V. and Celio, M. R., unpublished observations), but their electrophysiology has not yet been studied. In the hippocampal formation, however, while parvalbumin is indeed associated with a subset of fast-firing interneurons 52, calbindin-D28K is present in a subset of CA1 pyramidal neurons that can exhibit both current-evoked bursting activity or nonaccommodating responses depending on the pH of the extracellular medium 17. The potential for the buffeting of Ca2+ by calbindinD28K to influence voltage-operated Ca2+ channel activity has recently been examined by K6hr et al. 67 Dentate granule cells, depleted of their calbindinD28K content, had a lower whole-cell Ca2+ current than cells containing this protein. This interesting observation suggests that the loss of calbindin-D28K (or other major Ca2+ buffering systems) from a neuron may reduce Ca2+ entry and contribute to making the neuron less excitable. (These authors took advantage of one of the few experimental manipulations that have been shown to alter the concentration of calbindin in a particular neuron population - 'kindling'. Kindling stimulation is the process in which a train of initially subconvulsive electrical stimuli eventually leads to a full seizure response. During kindling, the calbindin-D28K level progressively declines until it is almost completely lost from dentate granule cells63'68.) It was noted earlier 1° that several calbindin-positive cell types (Purkinje cells, inferior olivary neurons and CA1 pyramidal cells) can produce Ca2+-based action potentials in their dendritic trees. It is not known whether other cells containing calbindin-D28K also have this property. It must be noted that the strong sequence conservation of calbindin-D28K and calretinin 65'69 suggests that they do something more than just binding and buffeting Ca 2+. However, searches for proteins that interact with calbindin-D28K, in either the presence or absence of Ca2+, have so far proved fruitless. Calretinin has recently been shown to inhibit phosphorylation of a single protein in neuronal membrane preparations 7°. A provocative recent finding suggests the possibility of a relationship between calbindinD28K and Caz+ channels; in particular with the P-type channel, originally identified in Purkinje cells. Antibodies against purified P-type channels labelled a number of populations of neurons that shared the feature of intense calbindin-D28K immunoreactivityTk

Modulation of the expression of calciumbinding proteins During development, CaBPs generally appear after neurons have started to differentiate, and often about the time when the neurons make contacts or become functional - although there are exceptions 2°'72-75. In addition, CaBPs may disappear from a functional system if it is disconnected, as for example in the TINS, VoL 15, No. 8, 1992

visual pathway after enucleation 76'77 However, this is such conditions a reduction of brain calbindin-D28K, not always the case: the levels of parvalbumin and which could be a reflection of nerve cell death, was calbindin-D28K in cerebellar Purkinje cells show no reported in patients with Alzheimer's disease 96'97 and change after complete disruption of the climbing fibre in those with Huntington's disease as. On the other projections, and striatal parvalbumin and calbindin- hand, calbindin-D28K-immunoreactive cells are relaD28K levels are not altered by chemical destruction of tively spared in the substantia nigra in people with the dopaminergic inputs from the substanfia nigra Parkinson's disease 99. Parvalbumin-containing neurons are less susceptible to neurodegeneration in Alz(Baimbridge, K. G., unpublished observations). The signal for synthesis of calbindin-D28K in heimer's disease according to some 1°°, but not all, cultured dorsal root ganglion cells has been studied by authors 1°1'1°2. Therefore, it is probable that the Droz and colleagues78-8°. They showed that the onset resistance of neurons to neurodegeneration has many of calbindin-D28K synthesis depends on a factor from different explanations and that CaBPs are only an muscle, which is the normal target organ of these aspect of the phenomenon. More details of the roles sensory neurons. If embryonic ganglion cells were of CaBPs in neurodegeneration were given in a recent deprived of their targets, or transplanted or cultured TINS review 1°3. before the production of calbindin-D28K, they did not make calbindin-D28K unless exposed to muscle factor. Concluding remarks However, if they were transplanted or cultured later, Although the neuroanatomical patterns of CaBPs some calbindin-D28K synthesis was maintained inde- seem at first to be clear cut, detailed studies show pendently of muscle. So for this neuronal type, at hetereogeneity of CaBP content, not only within the least, calbindin synthesis is indeed triggered by diverse populations of local inhibitory cells, but also contact with target tissue. within well-defined populations, such as pyramidal However, some cell types (including several brain cells in CA1 (Ref. 17), or dopaminergic cells in the nuclei, cochlear neuroepithelium and some immature substantia nigra 32. It seems likely that many more cells of retina) show a distinct earlier phase of regulatory influences on CaBP expression remain to calbindin-D28K immunoreactivity 74'75. Presumably be discovered. The complex distribution of these calbindin-D28K serves some special function during proteins has defied attempts to infer their function the development of these cells. Antibodies against from anatomical studies. Therefore, more direct calbindin-D28K can also be used to follow elusive manipulations of CaBP expression will have to be neurons during development, such as the Cajal- performed to resolve their roles. In the meantime, Retzius cells of cortex 19. antibodies against CaBPs are excellent tools for Extracellular Ca2+ and ocl,25-dihydroxyvitamin D3 distinguishing different neuronal populations in many (calcitriol) do not modulate the synthesis of calbindin- parts of the nervous system. D28K in brain 81, as they do in gut and kidney82. It has been reported that hippocampal calbindin-D28K is increased after the application of corticosterone 83 (but Selected references 1 Rogers, J. H. in Encyclopedia of A4olecular Biology (Kendrew, see Ref. 84); however, it is not affected by thyroid J. et al., eds), Blackwell Scientific (in press) hormones and malnutrition 85. Calbindin-D28K, as 2 Persechini, A., Moncrief, N. D. and Kretsinger, R. H. (1989) noted previously, is decreased after kindling-induced Trends Neurosci. 12, 462-467 epilepsy63'68'86. This manipulation has been reported 3 Dalgarno, D., Klevit, R. E., Levine, A. B. and Williams, R. J. P. (1984) Trends Pharmacol. 5ci. 4, 266-271 to increase the parvalbumin immunoreactivity in the 4 Cheung, W. Y. (1980) Science 207, 19-27 same brain region 87. However, this result has not 5 Hinrichsen, R., Burgess-Cassler, A., Chase-Soltvedt, B., been confirmed by direct measurement of parvalbuHennessey, T. and Kung, C. (1986) Science 232, 503-506 min by radioimmunoassay 84, although substantially 6 Rogers, J. H. (1987) J. Cell Biol. 105, 1343-1353 7 Winsky, L., Nakata, H., Martin, B. M. and Jacobowitz, D. M. elevated levels of parvalbumin have been observed in (1989) Proc. Natl Acad. 5ci. USA 86, 10139-10143 the cortex of the epileptic (E/) mouse 8s. Conversely, 8 Cello, M. R. (1990) Neuroscience 35, 375-475 calbindin-D28K mRNA is increased in the dentate 9 Braun, K. (1990) Prog. Histochem. Cytochem. 21, 1-64 granule cells after stimulation of the perforant path 89. 10 Jande, S. S., Maler, L. and Lawson, D. E. M. (1981) Nature It was not shown whether this led to raised levels of 294, 765-767 calbindin-D28K protein, or whether it was a futile 11 Jacobowitz, D, M. and Winsky, L. (1991) J. Comp. Neurol. 304, 198-218 response to increased protein degradation, which 12 Arai, R., Winsky, L., Arai, M. and Jacobowitz, D. M. (1991) would be consistent with the findings in kindled rats. J. Comp. Neurol. 310, 21--44

Calcium-binding proteins and neurodegeneration The distribution of CaBPs has also been used to support the hypothesis 9°'91 that intracellular CaBPs, functioning as Ca2÷ buffers, protect neurons from dying under experimental manipulations like ischemia 92, and neurotoxin application in vitro 9a'94. The neurotoxin sensitivities of neostriatal neurons that are immunoreactive to calbindin-D28K and parvalbumin vary; parvalbumin-containing neurons are more sensitive to kainic acid than calbindin-D28Kpositive cells95. These studies are particularly difficult to reconcile with those that addressed the fate of CaBPs in aging and neurodegenerative disorders. In TINS, Vol. 15, No. 8, 1992

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