Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons

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T.R. Soderling and V.A. Derkach – LTP: protein phosphorylation

32 Tan, S.E. et al. (1994) Phosphorylation of AMPA-type glutamate receptors by calcium/calmodulin-dependent protein kinase II and protein kinase C in cultured hippocampal neurons. J. Neurosci. 14, 1123–1129 33 Mammen, A.L. et al. (1997) Phosphorylation of the alpha-amino3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. J. Biol. Chem. 272, 32528–32533 34 Jia, Z. et al. (1996) Enhanced LTP in mice deficient in the AMPA receptor GluR2. Neuron 17, 945–956 35 Zamanillo, D. et al. (1999) Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805–1811 36 Derkach, V. et al. (1999) Ca21/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc. Natl. Acad. Sci. U. S. A. 96, 3269–3274 37 Davies, S.N. et al. (1989) Temporally distinct pre- and post-synaptic mechanisms maintain long-term potentiation. Nature 338, 500–503 38 Benke, T.A. et al. (1998) Modulation of AMPA receptor unitary conductance by synaptic activity. Nature 393, 793–797 39 Pereda, A.E. et al. (1998) Ca21/calmodulin-dependent kinase II mediates simultaneous enhancement of gap-junctional conductance and glutamatergic transmission. Proc. Natl. Acad. Sci. U. S. A. 95, 13272–13277 40 Roche, K.W. et al. (1996) Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16, 1179–1188 41 Kameyama, K. et al. (1998) Involvement of a postsynaptic protein kinase A substrate in the expression of homosynaptic long-term depression. Neuron 21, 1163–1175 42 Rosenmund, C. et al. (1994) Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal neurons. Nature 368, 853–856 43 Westphal, R.S. et al. (1999) Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science 285, 93–96 44 Cohen, P. (1989) The structure and regulation of protein phosphatases. Annu. Rev. Biochem. 58, 453–508 45 Blitzer, R.D. et al. (1998) Gating of CaMKII by cAMP-regulated

protein phosphatase activity during LTP. Science 280, 1940–1942 46 Makhinson, M. et al. (1999) Adenylyl cyclase activation modulates activity-dependent changes in synaptic strength and Ca21/ calmodulin-dependent kinase II autophosphorylation. J. Neurosci. 19, 2500–2510 47 Liao, D. et al. (1995) Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 48 Isaac, J.T. et al. (1995) Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427–434 49 Pessin, J.E. et al. (1999) Molecular basis of insulin-stimulated GLUT4 vesicle trafficking. J. Biol. Chem. 274, 2593–2596 50 Lledo, P.M. et al. (1998) Postsynaptic membrane fusion and longterm potentiation. Science 279, 399–403 51 Osten, P. et al. (1998) The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs. Neuron 21, 99–110 52 Nishimune, A. et al. (1998) NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 53 Song, I. et al. (1998) Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21, 393–400 54 Maletic-Savatic, M. et al. (1998) Calcium-evoked dendritic exocytosis in cultured hippocampal neurons. Part II: mediation by calcium/ calmodulin-dependent protein kinase II. J. Neurosci. 18, 6814–68211 55 Shi, S.H. et al. (1999) Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811–1816 56 Bhalla, U.S. and Iyengar, R. (1999) Emergent properties of networks of biological signaling pathways. Science 283, 381–387 57 Frank, D.A. and Greenberg, M.E. (1994) CREB: a mediator of longterm memory from mollusks to mammals. Cell 79, 5–8 58 Stewart, O. (1997) mRNA localization in neurons: a multipurpose mechanism? Neuron 18, 9–12 59 Wu, L. et al. (1998) CPEB-mediated cytoplasmic polyadenylation and the regulation of experience-dependent translation of alpha-CaMKII mRNA at synapses. Neuron 21, 1129–1139 60 Frey, U. and Morris, R.G.M. (1998) Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 21, 181–188

Complex interactions between mGluRs, intracellular Ca21 stores and ion channels in neurons Laurent Fagni, Pascale Chavis, Fabrice Ango and Joel Bockaert Metabotropic glutamate receptors (mGluRs) can increase intracellular Ca21 concentration via Ins(1,4,5)P3- and ryanodine-sensitive Ca21 stores in neurons. Both types of store are coupled functionally to Ca21-permeable channels found in the plasma membrane.The mGluR-mediated increase in intracellular Ca21 concentration can activate Ca21-sensitive K1 channels and Ca21dependent nonselective cationic channels. These mGluR-mediated effects often result from mobilization of Ca21 from ryanodine-sensitive, rather than Ins(1,4,5)P3-sensitive, Ca21 stores, suggesting that close functional interactions exist between mGluRs, intracellular Ca21 stores and Ca21-sensitive ion channels in the membrane. Trends Neurosci. (2000) 23, 80–88

Laurent Fagni, Pascale Chavis, Fabrice Ango and Joel Bockaert are at the CNRS-UPR 9023, 34094 Montpellier cedex 05, France.

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N NEURONS, intracellular Ca21 concentration can be transiently increased by two mechanisms: Ca21 influx through Ca21-permeable channels in the plasma membrane or the mobilization of Ca21 from intracellular Ca21 stores. Indeed, most neurotransmitters can trigger both mechanisms. Glutamate activates cationic channels, the so-called ionotropic glutamate-receptor channels, that induce cell depolarization and, hence, Ca21 influx through voltage-sensitive Ca21 channels. Some of these

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channels are also Ca21 permeable1. Glutamate can also activate G-protein- and phospholipase-C-coupled receptors, the so-called group-I metabotropic glutamate receptors (mGluRs; Refs 2,3). These receptors stimulate Ins(1,4,5)P3 synthesis and the mobilization of Ca21 from Ins(1,4,5)P3-sensitive intracellular Ca21 stores, which were first discovered in injected Xenopus oocytes4 and are now well characterized in mammalian neurons5–8. The group-I mGluR-mediated Ca21 responses have even

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been shown to generate slow EPSPs in cerebellar Purkinje cells9 and hippocampal pyramidal neurons10, and an IPSP in dopaminergic neurons of the ventral tegmental area11. Experiments have revealed that two genes code for group-I mGluRs: Grm1 and Grm5. Two other groups (II and III) of mGluRs have also been described, both of which are negatively coupled to adenylate cyclase12 (Box 1). Neuronal Ca21 stores with receptors that are sensitive to the plant alkaloid, ryanodine (the so-called ryanodinesensitive receptors – RyRs), provide a second source of intracellular Ca21 (Ref. 13). Indeed, there is increasing evidence to suggest that group-I mGluRs can mobilize intracellular Ca21 not only through Ins(1,4,5)P3-sensitive Ca21 stores, but also, and perhaps more efficiently, through these ryanodine-sensitive Ca21 stores. This article focuses on the neuronal determinants of the coupling between group-I mGluRs and RyRs, and the possible consequences of this coupling on membrane ion-channel activity and synaptic transmission.

Neuronal distribution of mGluRs and intracellular Ca21 pools The group-I mGluRs display distinct distributions in the CNS. For example, the cerebellum, and in particular the cerebellar Purkinje cells, displays much-stronger mglu1a-receptor immunoreactivity than most other regions of the brain14. In the hippocampus, mglu1areceptor immunostaining has been found to be strong in interneurons of the CA1 region and in some CA3 pyramidal cells, weaker in granule cells and absent in CA1 pyramidal cells14–16. However, the hippocampal CA1 pyramidal cells display clear mglu5-receptor immunolabeling15,17. This group-I mGluR immunolabeling was found in the soma and dendrites, but the density was highest on dendritic spines15. These distinct distributions might reflect different effector mechanisms between different cell types and in different neuronal compartments. Ultrastructural studies in the hippocampus and cerebellum have shown dense group-I mGluR immunostaining in postsynaptic membranes and densities, and in perisynaptic and extrasynaptic membranes14–18. Interestingly, substantial cytoplasmic immunostaining for the mglu1a receptor has been found to be also associated with organelles, especially the endoplasmic reticulum14,16. Studies that have compared the distribution of Ins(1,4,5)P3 receptors [Ins(1,4,5)P3Rs] with that of RyRs show differential localization of these receptors in the CNS. For example, in the cerebellum, Purkinje cells contain both Ins(1,4,5)P3Rs and RyRs, with especially prominent levels of Ins(1,4,5)P3Rs (Refs 19,20). In the hippocampus, Ins(1,4,5)P3Rs are most concentrated in the pyramidal cells of CA1, with substantially fewer in CA3 and only moderate levels in granule cells of the dentate gyrus19. The RyRs display an inverse pattern: the highest concentrations are in the dentate gyrus and CA3 region. As described in previous reviews13,21–23, neurons contain three types of RyRs (RyR1–3) and three types of Ins(1,4,5)P3Rs [Ins(1,4,5)P3R1–3], but predominantly Ins(1,4,5)P3R1 and RyR2. RyR2 has widespread distribution in the brain, whereas RyR1 is almost exclusively localized in cerebellar Purkinje cells and RyR3 predominates in the hippocampal CA1 region22. Immunohistochemical observations show that Ins(1,4,5)P3Rs and RyRs are co-localized on subsurface cisternae that originate from the endoplasmic reticulum and are distributed throughout neuronal cell compart-

ments. These compartments include axonal endings and dendritic spines13,19, although RyRs are predominantly located in the soma19,20,24,25. However, there are some exceptions: in the cerebral cortex, as well as in hippocampal CA3 and hilar regions, dendritic spines possess more RyRs than Ins(1,4,5)P3Rs (Refs 6,7,19). Whether Ca21 release in neurons originates from a functionally common or two distinct Ins(1,4,5)P3- and ryanodine-sensitive Ca21 pools is controversial. Thus, in cultured hippocampal5 and sensory neurons26, Ca21 mobilization caused by stimulation of receptors that are coupled to Ins(1,4,5)P3 synthesis occurs independently of the Ca21 mobilization caused by the RyR agonist, caffeine. This observation is consistent with the existence of two distinct Ca21 pools and is further supported by the identification of two pharmacologically distinct Ca21-ATPases in cerebellar granule cells, which can be distinguished by their sensitivity to 2,5-di-(ter-butyl)1,4-benzohydroquinone27. However, in these neurons an initial caffeine challenge reduces subsequent carbacholmediated Ins(1,4,5)P3-mediated Ca21 responses greatly. Reciprocally, an initial carbachol-mediated response reduces subsequent caffeine effects27,28. These observations suggest that RyRs and Ins(1,4,5)P3Rs share the same Ca21 pool. Regardless of whether the Ca21 pools are distinct in neurons, the integrity of RyRs seems to be necessary for Ins(1,4,5)P3R-mediated Ca21 release, as RyR antagonists have been shown to inhibit muscarinic ACh-receptorinduced Ins(1,4,5)P3 Ca21 responses in cerebellar granule cells28. It has therefore been suggested that muscarinic ACh-receptor stimulation mediates an initial small release of Ca21 from Ins(1,4,5)P3-sensitive Ca21 stores; this release then triggers the major component of the Ca21 response through ryanodine-sensitive Ca21 stores by a regenerative process called Ca21-induced Ca21 release13,23,28–30. Agonists (caffeine) and antagonists (ryanodine, ruthenium red, heparin, xestospongin C) of Ins(1,4,5)P3sensitive and ryanodine-sensitive Ca21-stores, which have been widely used to characterize intracellular Ca21release channels, are less specific than was generally thought31,32. However, despite of this lack of specificity, these drugs remain the only tools currently available to separate the physiological effects mediated by the Ins(1,4,5)P3-sensitive Ca21 store and the ryanodinesensitive Ca21-store.

Functional interactions between mGluRs, RyRs and L-type Ca21 channels In addition to activating intracellular Ca21 stores through Ins(1,4,5)P3 synthesis, group-I mGluRs can also activate RyRs independently of Ins(1,4,5)P3-mediated Ca21 mobilization. In cerebellar granule cells, mglu1receptor stimulation triggers Ca21 entry through L-type Ca21 channels in a ryanodine-dependent manner via a pertussis-toxin-insentive G protein33 (Fig. 1a). This effect is observed after blocking Ins(1,4,5)P3Rs with heparin, or in the presence of a high intracellular concentration of the potent Ca21 chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid acetomethylester (BAPTA), and it is not mimicked by intracellular dialysis of Ins(1,4,5)P3 (Ref. 33). Moreover, in cultured cerebellar granule cells, group-I mGluR responses are still obtained after the block of receptor-mediated Ins(1,4,5)P3 responses with pertussis toxin34 or after application of the Ins(1,4,5)P3R antagonist, xestospongine C (Ref. 36; TINS Vol. 23, No. 2, 2000

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Box 1.The metabotropic-glutamate-receptor family Vertebrate metabotropic glutamate receptors (mGluRs) are the products of eight genes and have been classified into three groups, according to their amino-acid sequence and the transduction mechanism that they activate. Groups I, II and III include mglu1 and mglu5 receptors, mglu2 and mglu3 receptors, and mglu4, mglu6, mglu7 and mglu8 receptor subtypes, respectively. Homologous group-II mGluRs have been cloned in Drosophilaa. All these receptors display 70% amino-acidsequence identity within a given group and 45% identity between different groups. Most of the genes for mGluRs are spliced and generate variants that differ in their C-terminal domain (Fig. I). The C-termini of mglu1a, mglu5a and mglu5b receptors are significantly longer than those of the other mGluR variants. Group-I mGluRs stimulate phospholipase C, whereas groups II and III inhibit activated adenylate cyclase. Other coupling mechanisms have been observed for mGluRs in neurons. These are the activation of phospholipase D, in hippocampal neuronsb, and the activation of phospholipase A2, in striatal neuronsc. The identities of the mGluRs involved in these effects have not been determined. The mglu6 receptor is found exclusively in ON-bipolar cells of the retina and activates a cGMP-phosphodiesterase, leading to closure of nonspecific cGMP-gated channels and cell hyperpolarizationd. Activation of adenylate cyclase by mGluRs has been reported in various cell linese, but has never been found in neurons. Nevertheless, several mGluR agonists can enhance

Group I

Group II

1a 1b 1c 1d 5a 5b 2 3 4a 4b 6

Group III

7a 7b 8a 8b trends in Neurosciences

Fig. I. C-terminal domains of the different mGluR splice variants. Only C-terminal domains that begin at the very end of the seventh transmembrane domain are represented here. For each mGluR subtype, the highly conserved domain of the different variants (black) and the specific domains for each splice variant (gray) are shown. The white domains in the mglu1a , mglu5a and mglu5b receptors represent the amino-acid sequence (PPXXFR) that is essential for the interaction between the receptor and Homer proteins. In the C-termini of the mglu4a and mglu4b receptors, only the first amino acid is common to the two sequences.

F. Ango and L. Fagni, unpublished observations). In the same preparation, direct measurement of intracellular Ca21 has shown that mGluRs can mobilize Ca21 from ryanodine-sensitive stores, without the generation of Ins(1,4,5)P3 (Ref. 37). Recently, mGluR-associated proteins, which provide putative material for such a functional interaction, have been identified38–41. These so-called Homer proteins (Box 2) are constitutively synthesized in neurons and might create a physical link between mglu1a, mglu5a or 82

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cAMP formation in neurons by potentiating the adenylatecyclase activation triggered by neurotransmitters that act on Gs-coupled receptorsf. Control of ion channels and transporters It is generally agreed that levels of group-I mGluRs are higher in postsynaptic membranes, whereas group-III receptors are predominantly found in axon terminals and group-II receptors display both presynaptic and postsynaptic locations, although there are exceptions in each of these groups. Group-I, -II and -III mGluRs have been found to inhibit voltage-activated Ca21 channels and to block synaptic transmissiong. These effects are generally found to be pertussistoxin sensitive and are probably mediated by the bg subunit of Go proteins that act on a specific binding site in non-L-type Ca21 channelsh. However, this hypothesis cannot apply to block of the L-type Ca21 channeli,j, as this channel does not display the consensus site that allows for the binding of Go protein bg subunitsh. Although in this particular case the mechanism of inhibition remains unknown, the a subunit of the Go protein might be involvedk. Group-I mGluRs activate a Ca21-dependent nonselective cationic conductance in hippocampal pyramidal neuronsl. Interestingly, this conductance can also be activated synaptically and might be involved in neuronal plasticitym. In neurons, group-I mGluRs inhibit the muscarinicreceptor-dependent K1 current, the current that is responsible for the afterhyperpolarization that occurs after an action potential and a leak K1 currentn. These effects result in excitatory responses, such as slowly developing depolarization and inward current, or inhibition of action-potential firing accommodation. At the presynaptic level, a protein kinase Cdependent mGluR-mediated inhibition of K1 channels facilitates glutamate release in area CA1 of the hippocampus, an effect that is rapidly desensitized by endogenous glutamateo. Group-I mGluRs can also activate Ca21-sensitive K1 and Cl2 channels, or the Na1–Ca21 exchangerp, which, in cerebellar Purkinje neurons, results in depolarization of the cellq,r. Modulation of ionotropic neurotransmitter receptors and synaptic plasticity Group-I mGluRs can modulate synaptic transmission by inhibiting GABAA receptors in the tractus solitarius nucleuss or by potentiating NMDA receptors, but not AMPA receptors, in striatal neuronst. This effect results from lessening the Mg21 block of the NMDA-receptor channel, caused by G-proteinmediated generation of phosphoinositides, a rise in cytosolic Ca21 levels and binding of Ca21 to calmodulinu. These changes might partly explain the potentiating effect of mGluR agonists on the induction of LTP in the hippocampusv,w. There is also a general agreement that the mglu1 receptor has an essential role in cerebellar LTD (Ref. x). References a Parmentier, M.L. et al. (1996) Cloning and functional expression of a drosophila metabotropic glutamate receptor expressed in the embryonic CNS. J. Neurosci. 16, 6687–6694 b Boss, V. and Conn, P. J. (1992) Metabotropic excitatory amino acid receptor activation stimulates phospholipase D in hippocampal slices. J. Neurochem. 59, 2340–2343

mglu5b receptors (Box 1) and Ins(1,4,5)P3Rs, as well as RyRs. Such protein–protein interactions should bring the RyR physically nearer to the mGluR, and could thus regulate the G-protein-mediated coupling between these receptors. The functional coupling between group-I mGluRs and RyRs that is observed in cerebellar granule cells can be extended to L-type Ca21 channels. This hypothesis is supported by the following experiments. Stimulation of the mglu1 receptor enhances L-type Ca21-channel activ-

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c Dumuis, A. et al. (1990) Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature 347, 182–184 d Nawy, S. and Jahr, C.E. (1990) Suppression by glutamate of cGMP-activated conductance in retina bipolar cells. Nature 346, 269–271 e Aramori, I. and Nakanishi, S. (1992) Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron 8, 757–765 f Pin, J.P. and Duvoisin, R. (1995) The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34, 1–26 g Anwyl, R. (1999) Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res. 29, 83–120 h Walker, D. and Waard, M.D. (1998) Subunit interaction sites in voltage-dependent Ca21 channels: role in channel function. Trends Neurosci. 4, 148–154 i Chavis, P. et al. (1994) The metabotropic glutamate receptor types 2/3 inhibit L-type Ca21 channels via a Pertussis toxinsensitive G-protein in cultured cerebellar granule cells. J. Neurosci. 14, 7067–7076 j Sayer, R.J. (1998) Group I metabotropic glutamate receptors mediate slow inhibition of calcium current in neocortical neurons. J. Neurophysiol. 80, 1981–1988 k Lledo, P.M. et al. (1992) Differential G protein-mediated coupling of D2 dopamine receptors to K1 and Ca21 currents in rat anterior pituitary cells. Neuron 8, 455–463 l Congar, P. et al. (1997) A long-lasting calcium-activated nonselective cationic current is generated by synaptic stimulation or exogenous activation of group I metabotropic glutamate receptors in CA1 pyramidal neurons. J. Neurosci. 17, 5366–5379 m Batchelor, A.M. and Garthwaite, J. (1997) Frequency detection and temporally dispersed synaptic association through a metabotropic receptor pathway. Nature 385, 74–77 n Charpak, S. et al. (1990) Potassium conductances in hippocampal neurons blocked by excitatory amino-acid transmitters. Nature 347, 765–767 o Rodriguez-Moreno, A. et al. (1998) Switch from facilitation to inhibition of excitatory synaptic transmission by group I mGluR desensitization. Neuron 21, 1477–1486 p Dumuis, A. et al. (1993) Stimulation of arachidonic acid release by glutamate receptors depends on Na1/Ca21 exchanger in neuronal cells. Mol. Pharmacol. 43, 976–981 q Staub, C. et al. (1992) Responses to metabotropic glutamate receptor activation in cerebellar Purkinje cells: induction of an inward current. Eur. J. Neurosci. 4, 832–839 r Linden, D.J. et al. (1994) trans-ACPD, a metabotropic receptor agonist, produces calcium mobilization and an inward current in cultured cerebellar Purkinje neurons. J. Neurophysiol. 71, 1992–1998 s Glaum, S.R. and Miller, R.J. (1993) Activation of metabotropic glutamate receptors produces reciprocal regulation of ionotropic glutamate and GABA responses in the nucleus of the tractus solitarius of the rat. J. Neurosci. 13, 1636–1641 t Pisani, A. et al. (1997) Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones. Br. J. Pharmacol. 120, 1007–1014 u Holohean, A.M. et al. (1999) Mechanisms involved in the metabotropic glutamate receptor-enhancement of NMDAmediated motoneurone response in frog spinal cord. Br. J. Pharmacol. 126, 333–341 v McGuinness, N. et al. (1991) trans-ACPD enhances long-term potentiation in the hippocampus. Eur. J. Pharmacol. 197, 231–232 w Otani, S. and Ben-Ari, Y. (1991) Metabotropic receptor-mediated long-term potentiation in rat hippocampal slices. Eur. J. Pharmacol. 205, 325–326 x Daniel, H. et al. (1998) Cellular mechanisms of cerebellar LTD. Trends Neurosci. 21, 401–407

ity recorded in cell-attached patches and, remarkably, this activity persists after the patch is excised to create the inside-out configuration33. This effect is blocked by application of ryanodine to the internal surface of the patch in the absence of an mGluR agonist (Fig. 1b), which suggests that a close functional interaction exists between the RyR and the plasma membrane Ca21 channel (although co-immunoprecipitation of the RyR and the L-type Ca21 channel has not yet been performed successfully in neurons). These experiments also indicate

that the mglu1 receptor triggers a functional coupling between RyRs and L-type Ca21 channels that is reminiscent of the crosstalk that exists between RyR1 and L-type Ca21 channels in skeletal-muscle cells42. These results are consistent with the intense RyR immunoreactivity found in the saccules near the plasma membrane of dendrites of hippocampal neurons19. Interestingly, a similar weak functional interaction has recently been reported to exist between Ins(1,4,5)P3Rs and Ca21-store-operated Ca21-permeable (Trp) channels in HEK293 and T3 cells35 (Fig. 1c). In these studies, the Ca21 store-operated channel, Trp, can be activated by the muscarinic ACh-receptor agonist, carbachol, in cellattached patches, or by Ins(1,4,5)P3 itself, in inside-out patches (Fig. 1d). Notably, in cerebellar granule cells, muscarinic ACh-receptor stimulation does not mimick the mglu1-receptor-induced coupling between RyRs and L-type Ca21 channels33, which suggests that some kind of functional specificity exists in the coupling between these two types of receptor (mGluR and muscarinic ACh receptor), intracellular Ca21 stores [ryanodine-sensitive Ca21 stores and Ins(1,4,5)P3-sensitive Ca21 stores, respectively]37 and plasma-membrane Ca21-permeable channels (L-type Ca21 channel and Ca21-store-operated Ca21 channel, respectively). So far, functional interactions between mGluRs and L-type Ca21 channels have been observed only in cultured cerebellar granule neurons33. It remains to be established whether a similar coupling exists in morecomplex preparations. At the moment no data allow us to invalidate this hypothesis and it would therefore be useful to examine this possibility in other neuronal preparations. Co-immunolabeling of membrane Ca21 channels and mGluRs in neurons has not yet been performed. Data obtained from separate preparations allow us to speculate only on their co-localization. Subcellular localization of mGluRs in neurons has already been briefly reviewed (above) and emphasizes the perisynaptic distribution of these receptors. Immunohistological studies performed in hippocampal pyramidal cells have shown discrete localization of L-type Ca21 channels in the cell body and in proximal dendrites43. Such localization patterns are theoretically incompatible with a close interaction between the L-type Ca21 channels and mGluRs. However, ‘slow’ Ca21 channels have also been detected in the dendritic fields of the hippocampus by receptor autoradiography44. Moreover, depending on the degree of back-propagation of action potential in the dendritic tree of some neurons, Ca21 transients can been detected in distal dendrites45–47. Thus, suprathreshold activation of neocortical48, but not hippocampal45,49,50 pyramidal neurons elicits Ca21 entry, partially through L-type Ca21 channels, in the entire neuron, including the distal primary, secondary and tertiary tuft branches of apical dendrites51. These morphological and functional studies suggest that if it is not a co-localization it could at least represent a close functional coupling between group-I mGluRs and L-type Ca21 channels in distal dendrites of cortical adult CNS neurons.

Activation of Ca21-sensitive K1 channels and nonselective cationic channels by mGluRs In neurons, Ca21-sensitive K1 channels seem to be located in the proximity of Ca21 channels52–57 and sense the intracellular Ca21 increase induced by group-I mGluR agonists at the submembrane level7,34,58,59. Interestingly, in cerebellar granule cells the mglu1-receptor-mediated TINS Vol. 23, No. 2, 2000

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initial hyperpolarization followed by depolarization. In these three types of neuron, the hyperpolarizaLCC CSKC mGluR tion results from activation of Ca212+ Cell-attached patch Inside-out patch Ca sensitive K1 channels and, at least in GX GPTX ventral tegmental area11 and pyraRyR midal neurons59, the hyperpolarizat-ACPD Heparin tion is ryanodine sensitive. These Ryanodine Ca2+ Ca2+ 0.8 results suggest that analogous Ins(1,4,5)P3 0.4 mechanisms, which involve func0 tional coupling between mGluR, 60 s Ins(1,4,5)P3R RyRs, voltage-activated Ca21 channels and Ca21-activated K1 channels, operate in adult CNS neurons (al(c) (d) though Ca21 entry through voltageCa2+ activated Ca21 channels has not always been examined). SOC 100 µM 2 µM MR Interestingly, Ca21 influx through Carb Ins(1,4,5)P3 1.0 21 Ins(1,4,5)P3R L-type Ca channels and the mobiGq lization of Ca21 from ryanodine0.5 sensitive Ca21 stores, in the absence 0.0 of an mGluR agonist, trigger the Ca2+ Ins(1,4,5)P3 slow afterhyperpolarization current 60 s trends in Neurosciences that follows the action potential in Fig. 1. Putative models of the interactions between metabotropic glutamate receptors or muscarinic ACh receptors, 62 and intracellular Ca21 stores and plasma-membrane ion channels. (a) The putative interactions between group-I CA3 hippocampal neurons . This 21 observation indicates that, in conmetabotropic glutamate receptors (mGluRs), intracellular Ca stores and membrane ion channels. The group-I mGluRs are coupled to a pertussis-toxin-sensitive G protein (GPTX) and to a pertussis-toxin-insensitive G protein (GX)34, in cultured trast to cultured cerebellar granule cerebral granule cells. GPTX is responsible for Ins(1,4,5)P3 synthesis, which in turn triggers the release of Ca21 from intra- cells, where the coupling between cellular Ca21 stores. Gx induces a tight coupling between ryanodine-receptors (RyRs) and membrane L-type Ca21 chan- RyRs and L-type Ca21 channels nels (LCC). The release of Ca21 from Ins(1,4,5)P3 receptors [Ins(1,4,5)P3Rs] might enhance the release of Ca21 from RyRs requires mglu1-receptor stimulation through a Ca21-induced-Ca21-release mechanism. These different sources of Ca21 contribute to the activation of Ca21- or activation of RyRs by caffeine33, sensitive K1 channels (CSKC) that are co-localized with LCC. This opening of LCC might also serve to replenish the intra- a similar coupling can be induced cellular Ca21 stores. The Ins(1,4,5)P3- and ryanodine-sensitive Ca21 stores are tentatively represented here as consisting by cell depolarization alone in the of a same Ca21 pool. However, whether these Ca21 stores belong to a same or distinct Ca21 pools is still controversial. hippocampus. (b) Activation of an L-type Ca21 channel [LCC in (a)] by bath application of the mGluR agonist, (1S,3R)-1-aminocyStimulation of group-I mGluRs clopentyl-1,3-dicraboxylate (t-ACPD; 400 mM) in a cultured mouse cerebellar granule cell. Channel open probability 21 (NPo) is monitored in a cell-attached patch and after excision of the patch into the inside-out configuration. The cell was not only activates Ca -dependent 1 K channels, but also, in the prestreated overnight with pertussis toxin. Inhibition of channel activity is produced by ryanodine (1 mM) but not by heparin 1 10,63 , (100 mg/ml). (c) The putative interactions between muscarinic ACh receptors (MRs), intracellular Ca21 stores and ion ence of K -channel blockers 21 channels in the membrane. MRs activate a Gq-type protein that is responsible for the synthesis of Ins(1,4,5)P3, which Ca -dependent nonselective catactivates Ins(1,4,5)P3Rs located on intracellular Ca21 stores. Activation of these receptors elicits opening of Ca21-store- ionic channels in hippocampal CA1 operated Ca21 (SOC or Trp) channels located on the plasma membrane. Opening of these SOCs might serve to replenish pyramidal cells. This effect is medithe Ca21 store. (d) Activation of SOC channels by bath application of carbachol (Carb) and Ins(1,4,5)P3 in a T3 cell. ated by a G-protein-dependent pro(b) Reproduced, with permission, from Ref. 33, and (c) reproduced, with permission, from Ref. 35. cess and the source of Ca21 is probably intracellular Ca21 stores, but the activation of Ca21-dependent K1 channels is blocked identity of the stores and whether Ca21 channels in completely by ryanodine and nifedipine, indicating the membrane are involved have not been studied. that it involves both RyRs and L-type Ca21 channels34. Functional consequences of the interaction between Moreover, in the same preparation a co-localization of mGluRs and RyRs mglu1-receptor-activated Ca21-dependent K1 channels 21 and voltage-activated Ca channels is found in cellAre these interactions involved in the refilling of Ca21 34,58 attached patches . The co-localization of these chan- stores? Ca21 entry through voltage-gated Ca21 channels nels and the ryanodine-dependent activation of both might participate in the refilling of Ca21 stores in hippovoltage-gated Ca21 channels33 and Ca21-activated K1 campal pyramidal cells5,28. In rat neocortical pyramidal channels34 by mglu1 receptors strongly suggests func- neurons, the decay timecourse of dendritic Ca21 trantional interactions between these proteins (Fig. 1a). Such sients is prolonged by blockers of Ca21-ATPase in the interactions could be crucial for the control of Ca21 endoplasmic reticulum (cyclothiazide and thapsigargin), suggesting an uptake of Ca21 into Ca21 stores in the homeostasis and cell excitability. Again, the above findings are derived from studies endoplasmic reticulum and clearance of dendritic performed in developing cultured neurons; one might Ca21 (Ref. 51). It is therefore possible that activation of question whether the model applies to adult neurons. L-type Ca21 channels by group-I mGluRs could be The following data were obtained from more-integrated involved in the refilling of ryanodine-sensitive Ca21 preparations (that is, adult brain-slice preparations) and stores in neurons. Indeed, such a role for Ca21 entry suggest that the observed effect might be physiologically might be complicated by the Ca21 content of ryanodinerelevant. Application of group-I mGluR agonists to baso- sensitive Ca21 stores if, as proposed in bullfrog sympalateral amygdala neurons60, hippocampal CA3 pyramidal thetic neurons, Ca21 entry participates in refilling cells61 and dopaminergic neurons of the ventral tegmen- ryanodine-sensitive Ca21 stores when these are depleted, tal area11 elicits biphasic responses, which consist of an or further increases cytosolic Ca21 concentration when

(a)

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NPO

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Box 2.The Homer proteins Different Homer proteins (Homer 1a, b and c, Homer 2 and Homer 3) have been cloned from mouse, Drosophila and human brain (Fig. Ia)a–d. The N-terminal regions are highly conserved between the different isoforms and highly homologous to the EVH1 domain of the Ena/ VASP protein familye. The N-termini of Homer proteins recognize a proline-rich sequence (PPXXFR) on the very distal C termini of the ‘long tail’ mglu1a, mglu5a and mglu5b receptors that is also present in the cytosolic region of ryanodine receptors (RyRs) and Ins(1,4,5)P3 receptors (Ins(1,4,5)P3Rs)c. The C termini of Homer proteins display a characteristic leucine-zipper motif that is responsible for the dimerization of these proteins via a coiled–coil interaction (Fig. Ia). These properties allow Homer proteins to create a physical link between mglu1a, mglu5a and mglu5b receptors and Ins(1,4,5)P3Rs directly (Fig. Ib). Figure I also suggests that, as RyRs display the Homer-protein recognition sequence (PPXXFR) of mGluRs and Ins(1,4,5)P3Rs, Homer proteins can also, theoretically, bind to RyRs. Only Homer 1a does not display any leucine-zipper sequence and therefore cannot dimerize. Instead, it competes with the other Homer proteins for mGluRs, Ins(1,4,5)P3R and RyRs, and thus plays the role of a dominantnegative regulator of these protein–protein interactions. Interestingly, all Homer proteins are constitutively synthesized in neurons, except for Homer 1a, which is produced during intense neuronal activity elicited by high-frequency stimulation that leads to LTP or convulsive seizuresb. Little is known about the physiological functions of Homer proteins in neurons. Recent work shows that transfection of a peptide homologous to Homer 1a significantly delays and slightly reduces Ca21 responses to mglu1-receptor stimulation in cerebellar Purkinje cellsc. As postsynaptic densities are enriched with Homer proteins and the expression of the gene encoding Homer 1a is induced during LTP, it is possible that these proteins are involved in synaptic plasticity. References a Kato, A. et al. (1998) Novel members of the Vesl/Homer family of PDZ proteins that bind metabotropic glutamate receptors. J. Biol. Chem. 273, 23969–23975 b Brakeman, P.R. et al. (1997) Homer: a protein that selectively binds to metabotropic glutamate receptors. Nature 386, 284–288 c Tu, J.C. et al. (1998) Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron 21, 717–726 d Xiao, B. et al. (1998) Homer regulates the association of group I metabotropic glutamate receptors with multivalent complexes of Homerrelated, synaptic proteins. Neuron 21, 707–716 e Gertler, F. et al. (1996) Mena, a relative of VASP and Drosophila enabled, is implicated in the control of microfilament dynamics. Cell 87, 227–239

ryanodine-sensitive Ca21 stores are full64. In addition to participating in refilling intracellular Ca21 stores, the influx of Ca21 from L-type Ca21 channels mediated by group-I mGluRs might induce a Ca21 release from the associated ryanodine-sensitive Ca21 stores, which would further increase intracellular Ca21 concentration. Group-I mGluRs modulate synaptic transmission and even generate synaptic potentials via mobilization of Ca21 from ryanodine-sensitive Ca21 stores. Thus, in dopaminergic neurons of the ventral tegmental area, a train of stimuli elicits an IPSP that consists of an early GABAB-receptor-mediated component followed by a slow mglu1-receptor-mediated component11. The latter component is blocked by ryanodine and results from activation of Ca21-dependent K1 channels. In the lamprey spinal cord, stimulation of group-I mGluRs facilitates action-potential-elicited presynaptic Ca21 transients, increases neurotransmitter release and enhances synaptically elicited EPSCs. This effect is blocked by ryanodine, although it is not associated with any increase in axonal Ca21 current65. These two examples

(a) EVH1 m-Homer m-Homer m-Homer m-Homer m-Homer m-Homer h-Homer d-Homer

1a 1b 1c 2a 2b 3 3

186 Amino acids 354 366 365 354 360 361 394 N

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C

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C Homer protein dimer N N

Ins(1,4,5)P3R

C

Ca2+ store

Interaction with PPXXFR sequence of mGluRs or Ins(1,4,5)P3R (or RyRs) Coiled—coil interaction trends in Neurosciences

Fig I. Homer proteins. (a) Primary structure of mouse (m), human (h) and Drosophila (d) Homer proteins. The red bands represent the conserved N-terminal regions that display the EVH1-like domain. The C-terminal region of Homer proteins (black) contains a leucine-zipper motif that is responsible for dimerization of the proteins through coiled–coil interaction, except for Homer 1a, which does not display the leucine-zipper sequence and therefore does not form dimers. (b) Protein– protein interactions mediated by Homer protein dimers. Arrows indicate competitions between the product of the immediate–early gene, Homer 1a, and the constitutive Homer dimers for metabotropic glutamate receptor (mGluR) and Ins(1,4,5)P3R (or RyR) binding sites that, theoretically, disrupt the link between the plasma membrane mGluR and intracellular Ca21-store receptor. Abbreviations: EVH1, Ena/VASP homologous domain 1, RyRs, ryanodine receptors.

suggest that the coupling between group-I mGluRs, RyRs and Ca21-dependent K1 channels is a component of glutamate-mediated synaptic transmission. However, the interaction between RyRs and L-type Ca21 channels observed in cerebellar granule cells (Fig. 1a,b) is not evident in these preparations. Tetanic stimulation of glutamatergic afferent fibers can generate a slow EPSP that results from activation of group-I mGluRs in both cerebellar Purkinje cells9 and hippocampal CA1 pyramidal neurons10. This mGluRmediated EPSP has been shown to result from activation of Ca21-dependent nonselective cationic channels, at least in hippocampal neurons10. Interestingly, because high-frequency stimulation of afferents is required to produce these mGluR-mediated EPSPs and group-I mGluRs (probably mglu5) are perisynaptically located in CA1 hippocampal pyramidal cell dendrites14–18, it has been suggested that after accumulation of glutamate in the synaptic cleft, spillover of glutamate molecules can reach the perisynaptic receptors and trigger the mGluRmediated response10. These observations suggest that TINS Vol. 23, No. 2, 2000

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mGluR-mediated EPSPs can be generated only under intense synaptic activity, for example, during tetanic afferent simulation that results in synaptic plasticity (see below) or pathological long-lasting excitotoxic depolarizations10. In cerebellar Purkinje cells, the mGluRmediated EPSP is potentiated by pre-depolarization of the neuron or Ca21-spike firing that is generated by climbing-fiber stimulation. The potentiation results from a transient rise in cytosolic Ca21 that is ‘memorized’ and promotes subsequent excitation through mGluRs for about two minutes. It has been suggested that the Ca21 memory trace is derived from intracellular stores and is boosted subsequently by Ca21 entry through local voltage-gated Ca21 channels9. This hypothesis, therefore, implies a crosstalk between mGluRs, intracellular Ca21 stores and Ca21 channels in the membrane. Long-term potentiation is a sustained increase in synaptic efficacy that has been extensively described in the hippocampus66,67. It occurs at glutamatergic synapses, after high-frequency stimulation of afferent fibers, and requires an increase in intracellular Ca21 concentration68 that seems to originate partly from mobilization of ryanodine-sensitive Ca21 stores69–72. Although it is generally agreed that the induction of LTP in the hippocampal CA1 region and dentate gyrus is dependent on activation of the Ca21 permeable NMDA receptors, it is not known whether activation of mGluRs is also required73–77. Studies from knockout mice have provided us with more insight: in mglu1-receptor knockouts, LTP can still be elicited at full strength in the NMDA-receptordependent pathways of area CA1 and dentate gyrus, but is impaired in the NMDA-receptor-independent pathway (mossy-fiber synapses) of area CA3 (Refs 78,79). The mglu5-receptor knockout mouse shows partially reduced LTP in the CA1 area of the hippocampus and dentate gyrus, but normal LTP in the mossy-fiber–CA3 synapses80. These data show that group-I mGluRs are not required for the induction of LTP, but are potential candidates for its modulation (mglu5 and mglu1 receptors in areas CA1 and CA3 of the hippocampus, respectively). The mechanisms by which group-I mGluRs modulate LTP might involve regulation of NMDA-receptor function (see Box 1 and Ref. 81). The following experiments suggest that a particular form of LTP might also involve the coupling between mGluRs and ryanodine-sensitive Ca21 stores. A form of LTP can be induced in the rat dentate gyrus by low-frequency stimulation of the medial perforant path in the presence of a low concentration (0.1 to 1 mM) of ryanodine69, which locks the RyR in a low-conductance open-configuration state82,83. This type of LTP is blocked by mGluR and L-type Ca21channel antagonists as well as by the RyR antagonist, ruthenium red69. Taken together, these data suggest that interactions between mGluR, RyR and L-type Ca21 channels in CNS neurons (Fig. 1a) could participate in synaptic plasticity. The reverse phenomenon of LTP is LTD (Refs 84,85), which affects glutamatergic synapses and is generally induced by low-frequency stimulation of afferents. Activation of mGluRs (Refs 69,78), which is associated with a transient rise in postsynaptic Ca21 levels86, is both necessary and sufficient to induce LTD in the cerebellum7,87–89. In the hippocampal formation90, it appears that presynaptic ryanodine-sensitive Ca21 stores are also required for the induction of LTD, as postsynaptic injection of ryanodine into single neurons does not block LTD in these neurons, whereas bath application 86

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of ryanodine, which permeates both presynaptic and postsynaptic membranes, blocks the induction of LTD in the same neurons91. However, it is unclear whether this type of synaptic plasticity requires a direct coupling between mGuRs and RyRs in presynaptic or postsynaptic elements.

Concluding remarks Group-I mGluRs are not only coupled to Ins(1,4,5)P3sensitive Ca21 stores but also to ryanodine-sensitive Ca21 stores. Activation of Ins(1,4,5)P3Rs and RyRs can induce an initial small release of Ca21 from Ins(1,4,5)P3-sensitive Ca21 stores that triggers further release of Ca21 from ryanodine-sensitive Ca21 stores, via a Ca21-induced Ca21 release. However, there is evidence to indicate that the mglu1 receptor is also coupled functionally to RyRs in cerebellar granule cells. This coupling is independent of Ins(1,4,5)P3R stimulation and might be modulated by Homer proteins. Moreover, there are indications that functional interaction exists between RyRs and plasmamembrane voltage-activated L-type Ca21 channels. This suggests that Ca21 entry into neurons is controlled in a manner that is reminiscent of the crosstalk seen between L-type Ca21 channels and RyR1 in skeletal-muscle cells42. These, and other observations, suggest the existence of close functional interactions between mGluRs, RyRs and L-type Ca21 channels. Indeed, in cultured cerebellar granule cells, complex interactions result in a spatially restricted increase in submembrane Ca21 concentration that is sensed by local Ca21-dependent K1 channels. The resulting intracellular ionic changes might be responsible for the modulation of synaptic transmission and plasticity, and even the generation of slow postsynaptic potentials in normal neuronal networks. Selected references 1 Sommer, B. and Seeburg, P.H. (1992) Glutamate receptor channels: novel properties and new clones. Trends Pharmacol. Sci. 13, 291–296 2 Nicoletti, F. et al. (1986) Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus. J. Neurochem. 40, 40–46 3 Sladeczek, F. et al. (1985) Glutamate stimulates inositol phosphate formation in striatal neurons. Nature 317, 717–719 4 Sugiyama, H. et al. (1987) A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature 325, 531–533 5 Murphy, S.N. and Miller, R.J. (1989) Two distinct quisqualate receptors regulate Ca21 homeostasis in hippocampal neurons in vitro. Mol. Pharmacol. 35, 671–680 6 Takechi, H. et al. (1998) A new class of synaptic response involving calcium release in dendritic spines. Nature 396, 757–760 7 Finch, E.A. and Augustine, G.J. (1998) Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites. Nature 396, 753–756 8 Whitham, E.M. et al. (1991) Inositol 1,4,5-trisphosphate-stimulated calcium release from permeabilized cerebellar granule cells. Br. J. Pharmacol. 104, 202–206 9 Batchelor, A.M. and Garthwaite, J. (1997) Frequency detection and temporally dispersed synaptic association through a metabotropic receptor pathway. Nature 385, 74–77 10 Congar, P. et al. (1997) A long-lasting calcium-activated nonselective cationic current is generated by synaptic stimulation or exogenous activation of group I metabotropic glutamate receptors in CA1 pyramidal neurons. J. Neurosci. 17, 5366–5379 11 Fiorillo, C.D. and Williams, J.T. (1998) Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394, 78–82 12 Pin, J.P. and Duvoisin, R. (1992) The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34, 1–26 13 Berridge, M.J. (1998) Neuronal calcium signalling. Neuron 21, 13–26 14 Baude, A. et al. (1993) The metabotropic glutamate receptor (mGluR1 alpha) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 11, 771–787 15 Lujan, R. et al. (1996) Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8, 1488–1500

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Acknowledgements The authors’ research is supported by grants from CEE BIOMED, CEE BIOTECH, Synthelabo, DRET, AFM and Bayer. The authors thank J.P. Pin and L. Vitkovic for critically reading the manuscript, and M. Passama for the figures.

BOOK

73 Cohen, A.S. et al. (1998) Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phospholipase C. Hippocampus 8, 160–170 74 Bashir, Z.I. et al. (1993) Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors. Nature 363, 347–350 75 McGuinness, N. et al. (1991) Trans-ACPD enhances long-term potentiation in the hippocampus. Eur. J. Pharmacol. 197, 231–232 76 Manzoni, O. et al. (1994) MCPG antagonizes metabotropic glutamate receptors but not long-term potentiation in the hippocampus. Eur. J. Neurosci. 6, 1050–1054 77 Chinestra, P. et al. (1993) (RS)-a-methyl-4-carboxyphenylglycine neither prevents induction of LTP nor antagonizes metabotropic glutamate receptors in CA1 hippocampal neurons. J. Neurophysiol. 70, 2684–2689 78 Conquet, F. et al. (1994) Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1. Nature 372, 237–243 79 Aiba, A. et al. (1994) Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice. Cell 79, 365–375 80 Lu, Y-M. et al. (1997) Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 17, 5196–5205 81 Contractor, A. et al. (1998) Direct effects of metabotropic glutamate receptor compounds on native and recombinant N-methylD-aspartate receptors. Proc. Natl. Acad. Sci. U. S. A. 95, 8969–8974

82 McPherson, P.S. et al. (1991) The brain ryanodine receptor: a caffeine-sensitive release channel. Neuron 7, 17–25 83 Meissner, G. (1986) Ryanodine activation and inhibition of the Ca21-release channel of sarcoplasmic reticulum. J. Biol. Chem. 261, 6300–6306 84 Daniel, H. et al. (1998) Cellular mechanisms of cerebellar LTD. Trends Neurosci. 21, 401–407 85 Ito, M. et al. (1982) Climbing fibre induced depression of both mossy fibre responsiveness and glutamate sensitivity of cerebellar Purkinje cells. J. Physiol. 324, 113–134 86 Konnerth, A. et al. (1992) Brief dendritic calcium signals initiate long-lasting synaptic depression in cerebellar Purkinje cells. Proc. Natl. Acad. Sci. U. S. A. 89, 7051–7055 87 Kasano, K. and Hirano, T. (1995) Involvement of inositol trisphosphate in cerebellar long-term depression. NeuroReport 6, 569–572 88 Khodakhah, K. and Armstrong, C.M. (1997) Inositol trisphosphate and ryanodine receptors share a common functional Ca21 in cerebellar Purkinje cells. Biophys. J. 73, 3349–3357 89 Inoue, T. et al. (1998) Type 1 inositol 1,4,5-trisphosphate receptor is required for induction of long-term depression in cerebellar Purkinje neurons. J. Neurosci. 18, 5366–5373 90 Kobayashi, K. et al. (1996) Presynapic long-term depression at the hippocampal mossy fiber–CA3 synapse. Science 273, 648–650 91 Reyes, M. and Stanton, P.K. (1996) Induction of hippocampal longterm potentiation requires release of Ca21 from separate presynaptic and postsynaptic intracellular stores. J. Neurosci. 16, 5951–5960

REVIEWS Brain Maps: Structure of the Rat Brain (2nd edn) by L.W. Swanson, Elsevier, 1998. NLG 190.00, euro 86.22, $90.00 (vii + 268 pages, 2 CD-ROMs) ISBN 0 444 82785 4 This work appears with the subtitle ‘A Laboratory Guide with Printed and Electronic Templates for Data, Models and Schematics’. It condenses, in revised and technically actualized format, the previous printed and electronic editions of this atlas1,2. The buyer receives 2 CD-ROMs with images and diagrams, and a book that is about half the size of the previous extra-large printed edition. The book contains interpreted drawings (73 cross-sections), introductory text, annotated nomenclature tables (a valuable asset), a list of abbreviations, references and an index. The author is a well-known scholar in the field of rat neuroanatomy. The main value of this book, which is addressed to the nonspecialist, is that it makes available the expertise of Swanson, in a way that assists in making practical use of his delineations for mapping and reporting new descriptive or experimental results. Regardless of the potential inaccuracies that might result from forcing sets of data from brains cut through various sectional planes or of different sizes into these drawings, it will be much used. However, the introductory text cautions about these difficulties and gives detailed procedural suggestions for correct interpretations. I found working with the CD-ROM somewhat irritating. Opening the successive section levels in Adobe Illustrator 8.0® (bought for the occasion) seemed to take considerable time. The emerging images were too small and, at the point where both cytoarchitectony and drawings were

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jointly visible, I could not read most of the labels, nor accurately distinguish structural landmarks in the screen of my laptop. When the smaller labels became legible, the attached histological sections became pixelated, which hampered corroboration of the smaller delineations and identifications offered by the author. It is possible that working with a larger screen and higher computing speed, and making the image resident in the computer memory, might resolve these difficulties. Another irritating feature of this atlas is the changing orientation of the identity tags on the delineated structures. The author apparently thinks that readability is thus improved, which might be true in some cases, but the measure seems arbitrary in many others. The readers will frequently desist from subjecting their neck and brain to the necessary contortions. One CD-ROM also contains flatmap templates that are used to represent cell groups and tracts. These contain many of the personal (didactic?) conceptions of the author about the topological relationships of brain parts. I noted that any topological insights offered in recent years by the prosomeric approach – notably the zona limitans intrathalamica – are carefully eschewed. No wonder that, when judging from a different viewpoint3, one observes some clearcut aberrations. There are several examples to be considered. (1) The unnaturally stretched ventral thalamus layout [see ventral geniculate nucleus (GV), zona incerta (ZI) and reticu-

lar nucleus (R)]; and, moreover, the vinculation of ventral thalamus, epithalamus and lateral hypothalamus by the author to a ‘reticular core’ that extends into brainstem tegmentum. This seems to be weak functional reasoning applied to poor morphology (see ‘Annotated Nomenclature’, p. 210). (2) The pretectal and isthmic formations are forced to belong to the midbrain (I fail to understand Swanson’s unwillingness to adapt to recent conclusive developmental data on the isthmus – or on the ventral thalamus, for that matter). (3) The optic tract is shown to run longitudinally along the midline of the hypothalamus down to midbrain levels and then transversely into the visual neuropiles; these seem grouped ad hoc at this spot. (4) The pyramidal tract and thalamocortical projections seem to have to traverse the topologic gulf that separates thalamus from the telencephalon. (Do they exit the brain and enter again? The old naive idea of a tele-diencephalic adhesion was abandoned by embryologists long ago.) The basic problem seems to be that Swanson’s flatmaps largely discard the embryonic radial relationships of periventricular to subpial structures (for example, ZI–R–GV) and thus the flatmaps emerge as not being topological at all. They represent a bluntly ‘squashed’ brain, adapted to preconceived simplistic notions (interbrain, etc.). Though there are aspects of the templates that are less deviant from established knowledge, I tend to doubt that these constructions ‘are especially useful for comparing gross expression patterns’, as stated in the preface. Such a use is not recommended for beginners. However,