A new mechanism for glutamate receptor action: phosphoinositide hydrolysis

A new mechanismfor glutamate receptor action: phosphoinositidehydrolysis Fritz Sladeczek, M a x R6casens and JoEl Bockaert

Most of the effects of excitatory amino acids (EAAs) have been attributed to their interactions with three main ionotropic receptors: the N-methyl-D-aspartate (NMDA), the quisqualate (Q) and the kainate (If) receptors. In this review, we discuss data showing that in several experimental preparations (neuronal and glial cultures, brain slices, synaptoneurosomes), activation of EAA receptors stimulates the inositol phosphate (IP)/diacylglycerol (DAG) second messenger pathway, and that novel EAA receptots are implicated. They include Qand ibotenate (IBO)-preferring receptors, which are potent stimulators of IP production, mobilize intracellular C ~ + stores and have specificities distinct from other EAA receptors already described. The activity of this novel class of EAA receptors is high during the synaptogenesis period and low in adult brain. NMDA and K receptors also stimulate IP production, although this effect is probably indirect. The possible functions of EAA receptors associated with the production of IP/ DAG are discussed.

channels (ionotropic receptors5), as well as on Fritz Sladeczek,Max receptors that are coupled through GTP-binding R6casensand Jo#l proteins (G proteins) to ion channels or to enzymes Bockaertare at the producing second messengers. Acetylcholine is a good Centre CNRSexample of such a neurotransmitter, acting on nicotinic INSERMde receptors (ionotropic receptors) as well as on PharrnacologieEndocrinologle, Rue muscarinic receptors coupled to K + channels or de la Cardonille, adenylate cyclase through two different G proteins 6' 7 34094 Montpe//ier (Gk and Gi, respectively). Recent reports indicate that Cedex, France. Glu receptors can also regulate the production of second messengers in neurons, cAMP and cGMP have already been reported to be associated, although indirectly, with EAA receptor action8'9. Furthermore, it is likely that the increase in intracellular Ca 2+ associated with NMDA receptor action tnggers second messenger functions 1°. The evidence that Glu receptors could use phosphoinositides (PI) to generate second messengers is more recent. It is now well known that when some external signals such as hormones, neurotransmitters and growth factors bind to their In vertebrates, excitatory amino acids, primarily L- receptors, they stimulate the hydrolysis of phosglutamate (Glu) and L-aspartate (Asp), appear to be phatidylinositol 4,5-bisphosphate (PIP2) to give dithe major excitatory neurotranslnitters in the CNS 1. acylglycerol (DAG) and inositol 1, 4, 5-trisphosphate Selective electrophysiological responses to agonists (IP3), both of which function as second messengers. have been used to define the three main receptors - DAG is a second messenger operating within the NMDA, K and Q (Table I). The NMDA receptor plane of the membrane to stimulate protein kinase is the only one for which selective competitive C (PKC), whereas IP3 is released to the cytosol to antagonists have been synthesized. Among these, mobilize Ca 2+ from the endoplasmic reticulum :°. In DL-2-amino-5-phosphonovaleric acid (APV) or 3- most cases, PIP2 is hydrolysed by a phosphodiester(+) -2 -(carboxypiperazin-4-yl)-propyl-1-phosphonic acid ase, termed phosphoinositidase: 1, which is coupled to (CPP) are the most potent 1. These antagonists surface receptors by means of a G protein (Gp). are inactive on Q and K receptors. Q and K receptors However, in some systems, the phosphoinositidase can both be blocked by poor selective antagonists can be directly stimulated by the increase in such as L-glutamic acid-diethyl-ester (GDEE), 5'-D- intracellular concentrations of Ca 2+ ([Ca2+]i) and glutamylglycine (yDGG), or by more selective ones perhaps Na + (for reviews, see Refs 10, 11). such as oL-D-glutamyl-aminomethylsulphonate(GAMS) Two years ago, we demonstrated that EAAs and two quinoxalines2 [6, 7-dinitro-quinoxaline-2, 3- stimulate the production of inositol phosphates (IPs) dion (FG9041) and 6-nitro-7-cyanoquinoxaline-2,3-dion (FG9065)]. In TABLE I. Vertebrate excitatory amino acid receptor subtypes addition to the three classical Agonists NonIons involved EAA receptors, a fourth class has Receptor (most Competitive competitive AIIosteric in ionotropic Second been postulated which may be type selective) antagonists antagonists agonist functions messengers specifically activated by 2-amino-4NMDA Ca2+(* **) NMOA APV Ketamine Glycine Ca2+ phosphonobutyrate (APB). Such a IBO APH MK-801, PCP K+ (1,4,5)IP3/DAG(**) receptor triggers hyperpolarization CPP SKF 10047 Na ÷ cGMP?(**) in retina bipolar cells~ and depresses Magnesium synaptic transmission in hippoK K C£+(*) campus, probably by acting on Domoate yDGG, GDEE, JSTX Na +, K+ (1,4,5)IP3/DAG(*) presynaptic terminals 4 (it is difficult GAMS to know whether APB behaves as FG9065 an agonist or an antagonist in this Q Q yDGG, GDEE, JSTX Na +, K+ (1,4,5)IP3/DAG(?) case). Ca2+(?) AMPA GAMS Our conceptions about the transFG9065 duction mechanisms associated with Qp Q No antagonist (1,4,5)IP3/DAG(***) neurotransmitter receptor actions IBOp IBO APB, (1,4,5)IP3/DAG(***) have rapidly changed over the past phosphoserine few years. It is now clear that a single neurotransmitter can act on APH: D-2-amino-4-phosphonobutyrate; PCP: Phencyclidine AMPA: c~-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors that are themselves ion ( . . . . . . . . ) denote level of efficiency in producing second messengers. TINS. Vol. 11, No. 12, 1988

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Quisqualate Gl utamate a= 100 N-methyI-D-aspartate (.9 Kainate T/ E

blocked by an injection of EGTA and is probably the result of the O O l 1--~ following cascade of events: (1) O activation of Q receptors; (2) A ~ " ~ f production of IP3; (3) mobilization of intracellular Ca 2+ stores; and (4) activation of a Ca 2+-dependent Clchannel. Although it has not been E directly demonstrated that Q can indeed increase PI hydrolysis in ~t 50 these oocytes, it is likely that the Q O receptors that have been expressed are similar to the Q-preferring E receptors coupled to PI hydrolysis 0 in brain cells. The Q-induced 13._ PI hydrolysis in striatal neurons 12 and cerebellar granule cells 13, and // i I I I I I I the Q-induced electrophysiological 0 --9 --8 --7 --6 --5 --4 --3 effect in Xenopus oocytes 22 were --Log [agonist] (M) not mediated by NMDA receptors, Fig. 1. Dose response for EAA stimulation of inositol phosphate accumulation in mouse striatal since APV, a specific NMDA neurons in primary culture. Cells were cultured for 11-14 clays (as described in Ref. 46) in a serum- receptor antagonist, did not block free medium containing 5 #Ci/ml myo-[3H]inositol. They were then exposed to increasing these responses. Now, a pertinent concentrations of EAA and the total content of inositol phosphates was determined. Results are question is whether or not the expressed as a percentage of the response induced by 10 % Glu. Glu stimulated a three- to four- Q effect on PI hydrolysis is medifold increase in inositol phosphate production. (Taken,with permission,from Ref. 12.) ated by the classical ionotropic Q receptor. in primary cultures of mouse striatal neurons 12. In two models, Xenopus oocytes '~'~ and rat brain Similar findings have now been reported in rat synaptoneurosomes is, pharmacological studies clearbrain cerebellar granule cells in culture 13, rat brain ly indicate that it is not. (1) In rat brain synaptoneurslices 1~-16, rat brain synaptoneurosomes 17'18 (synapto- osomes 18, GDEE and yDGG, two non-selective neurosomes are synaptosomes with attached resealed antagonists of EAA ionotropic receptors (Table I) postsynaptic entities 19) and astrocyte-enriched cul- were inactive in blocking the Q-induced PI hydrolysis. tures prepared from neonatal rat cortex 2°. Although GDEE was also inactive on the Q-induced CIthis field has not yet been fully investigated, the conductance in Xenopus oocytes. (2) GAMS and questions we would like to raise here are: (1) Which FG9065, two antagonists showing some selectivity type of EAA receptors are involved in the regulation for non-NMDA (Q and K) versus NMDA receptors, of IP production? Are they different from EAA were ineffective in blocking the Q-induced IP receptors coupled to ion channels? (2) What do we formation in rat brain synaptoneurosomes 1~. (3) The know about the mechanisms responsible for the EAA- Joro spider toxin that blocks ionotropic non-NMDA activated IP biosynthesis? (3) What is the functional responses (Table I) did not suppress the Q-response significance of the EAA receptors mediating IP/DAG presumably mediated by IP3 production in Xenopus oocytes 22. (4) DL-o~-amino-3-hydroxy-5-methyl-4formation both in young and adult brain? isoxazole propionic acid (AMPA), a drug as potent The s t i m u l a t i o n of PI h y d r o l y s i s by EAA as Q on the Q ionotropic receptor 2:~, was less i n v o l v e s a novel class of r e c e p t o r s t h a t potent by a factor of about 300 compared with Q in mobilize i n t r a c e l l u l a r Ca 2+ s t o r e s increasing PI hydrolysis 1~ (Fig. 2). Similarly, in In primary cultures of mouse striatal neurons, striatal neurons, AMPA was very weak in stimulating EAAs stimulate the production of IP with the IP production (Sladeczek, F., unpublished obserfollowing rank order of potency: Q > Glu > NMDA, K vations). In cerebellar granule cells, GDEE and yDGG (Fig. 1). The EC5os of these agonists were 0.16 btM, were also unable to inhibit the Q-induced IP 4 btM, 15 ~tM, and 10 btM, respectively (Fig. 1). Glu and stimulation 13. Thus the Q receptor that activates the Q stimulated basal IP production by 300-400%, inositol phosphate pathway is likely to be a new type whereas NMDA and K stimulations were about 40% of EAA receptor. We will refer to this receptor as Qp of the maximal Glu response (Fig. 1). In the same (Table I). preparation, carbachol, neurotensin and noradrenaline If this receptor does exist, it should be able to stimulated IP production by 700%, 200% and 400% of mobilize intracellular Ca 2+ stores, and this has basal levels, respectively21. Such a Q-preferring recently been observed (Murphy, S. N. and Miller, response has now been described in primary cultures R. J., pers. commun.). In primary cultures of hippoof cerebellar granule cells ~3, in brain synaptoneuro- campal neurons, they have shown that in the absence somes I7q~, as well as in astrocytes in culture 2°. In all of external Ca 2+, Q, IBO and Glu but not NMDA, K these systems, total IP production was measured in or AMPA were able to produce a clear spikethe presence of Li +. In Xenopus oocytes, a particular like intracellular Ca 2+ increase, which under these Glu receptor was expressed after injection of rat brain conditions presumably reflects Ca 2+ release from mRNA ~2. This receptor is specifically stimulated by Q intraceUular pools. The pharmacology of the Q and triggers an increase in CI- conductance. This receptor mobilizing intracellular Ca 2+ was also response can be mimicked by an injection of IP3 and different from the Q ionotropic receptor and was 0

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similar to the pharmacology of the Qp receptor (i.e. absence of blocking effect of GAMS, GDEE, absence of agonist properties of AMPA) (Murphy, S. N. and Miller, R. J., pets. commun.). The following experiments suggest that, in addition to this Qpreceptor, another receptor, which prefers IBO as agonist, is also coupled to the production of IP. In brain slices obtained from rat hippocampus, two groups described very potent effects of IBO on PI turnover 14-]6. Interestingly, APB, a drug acting on the fourth receptor described in electrophysiological experiments 3'4, and phosphoserine were antagonists of the IBO response in hippocampus ]4-16 (although they were agonists in young rats15). There are no data to determine whether or not the IBO-mediated IP response is triggered by the APB-stimulated EAA receptor described in electrophysiological experiments 3'4. The IBO receptor associated with the IP response is likely to be different from the NMDA receptor, since APV was inactive on IBO-induced IP production in hippocampal slices 14. Finally, it is important to decide if the IBO-mediated IP response is triggered by a receptor different from the one implicated in the Q-mediated IP response. Some data suggest that the PI-coupled receptors stimulated by Q and IBO are indeed different: (1) IBO very weakly stimulates IP production in rat brain synaptoneurosomes (R6casens, M., unpublished observations), whereas it is more potent than Q in hippocampal slices 14-16. (2) The anatomical distributions of Q and IBO in brain are different. The IBO response was mainly localized in hippocampus 14-]5, whereas the Q-preferring response has been found in striatal neurons la, cerebellar granule cells 13, and synaptoneurosomes of the whole forebrain 17-1s. (3) In contrast to the Qp response ]3' ]7,18,22, IBO-induced IP production is blocked by APB 15. We will refer to the IBO-preferring receptors triggering the IP response as IBOp receptors. NMDA and K receptors can also affect PI hydrolysis In several systems, such as striatal neurons in culture 12, cerebellar granule cells 13 and synaptoneurosomes 17'18, stimulation of NMDA receptors leads to an IP response that is blocked by APV and regulated by Mg2+ (Refs 24, 25). These regulations correspond to those observed for the classical NMDA responses measured electrophysiologically26. Similarly, K has been reported to increase IP formation slightly in striatal neurons 12, cerebellar granule cells 13, and synaptoneurosomes 17. PI hydrolysis mediated by the ionotropic Q receptor has not been reported, but could have been masked by the Q receptor specifically coupled to this pathway. How do EAA receptors trigger increased PI hydrolysis in brain? The possibility of a direct coupling of Qpreceptors with Gp is probable. It is supported by the observations that the Q electrophysiological response in Xenapus oocytes22, the Q-mediated IP formation in cerebellar granule cells (Nicoletti, F., pers. commun.), as well as the mobilization of intracellular Caa+ stores in hippocampal neurons (Murphy, S. N. and Miller, R. J., pers. commun.) are blocked by pertussis toxin (PT). PT is an exotoxin of Bordetella pertussis known TINS, Vol. 11, No. 12, 1988

to block the action of some transducing G proteins (such as Gi and Go and some, but not all Gp, which are known to couple membrane receptors and their effectors). In contrast, we have been unable to block the Qp response in striatal neurons with PT. This can indicate that Qp receptors can be coupled to phosphoinositidase by Gp proteins that are either sensitive or insensitive to PT. The mechanisms by which the IBOp receptor increases the IP response are almost completely unknown. This is also true of the NMDA-mediated IP response. It is possible that the NMDA effects are mediated by an increase in [Ca2+]i, which could lead to a direct activation of the phosphoinositidase 27-29. Such a situation has been described for the guanylate cyclase activation mediated by NMDA receptors 9, but seems to be rejected by Wroblewski et al. a4 to explain the effect of NMDA on PI hydrolysis in cerebellar cells. However, more data are required to establish clearly the dissociation between the effects of NMDA on PI hydrolysis and on cellular Ca 2+ entry. The intriguing possibility of a direct coupling of NMDA receptors to a G protein is supported by the observation that [3H]Glu-binding to NMDA receptors is sensitive to guanyl nucleotides 3°. The small effect of the K or IP response could also be explained by the observation that K is able to raise [Ca2+]i in neurons al. Obviously, further investigations are required to understand the mechanisms by which EAAs stimulate PI hydrolysis. Are EAAs able to reduce the PI response of other neurotransmitters? The possibility that EAAs (particularly via NMDA and K receptors) can reduce IP production stimulated by other neurotransmitters is far from clear. In adult rat hippocampal slices, Baudry et al. 32 found that EAAs reduce IP produced by carbachol, histamine, and K +, but not that produced by norepinephrine. 250

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[Ag0nist] (M) Fig. 2. Dose response for Q and AMPA stimulation of inositol phosphate accumulation in rat forebrain synaptoneurosomes. 5ynaptoneurosomes were prepared as described in Ref. 19. PI was labelled with myo-[3H]inositol and IP production determined (as described in Ref. 17). Accumulation of IP is expressed as percentage stimulation above basal levels. (Taken, with permission, from Ref. 18.) 547

Acknowledgements However, in the same system, Nicoletti et al. 15 found review that not only NMDA but also Qp and IBOp We thank P. Ascher and J. P. Pin for commenting on the manuscript and for interesting discussions. R. J. Miller and H. Sugiyama for access to unpublished manuscripts. Mrs A. L. TumerMadeuf and Miss P. Costagliola are thanked for their excellent work in the preparation of the manuscript Work in the author's laboratory was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la SantE et de la Recherche MEdica/e (INSERM) as we// as by grants from the Bayer Pharmaceutical Company (France).

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that only the norepinephrine IP response was inhibited by EAAs. In striatal neurons, we have found that intensive stimulation of NMDA and K receptors can reduce carbachol but not norepinephrine and neurotensin IP responses 33. In all cases, 30-40 min stimulation periods were used. In striatal neurons, the NMDA-induced inhibition of the IP response was accompanied by a significant loss of the cytosolic enzyme lactate dehydrogenase (LDH) into cell supernatant33. It is therefore possible that EAAinduced inhibitions of PI hydrolysis stimulated by other neurotransmitters is due to cytotoxic action of EAAs.

receptors can activate the IP/DAG pathway and therefore kinase C. Similarly, LTP has also been shown to be associated with an increased labelling of P142'43. Finally, Ito et al.44 have shown that in CA3 but not in CA1 hippocampal neurons, PT suppressed induction of LTP. Whether or not this is due to a blockade of the Qp receptor action which is also sensitive to PT in this structure (Murphy, S. N. and Miller, R. J., pers. commun.) remains to be demonstrated. In addition to these long-lasting cl~anges resulting from PI hydrolysis, an increase in IP3 production induced by EAA is likely to cause a rapid increase in the release of Ca2+ from some intracellular pools leading to relatively rapid responses. ConsiderPossible physiological roles of EAA-stimulated ing the mechanism of action of ionotropic receptors PI hydrolysis such as NMDA and K, this intracelMar release of It is likely that the IP/DAG second messenger Ca2+ is probably negligible in comparison to the Ca2+ system plays an important physiological role in the coming from the extracellular compartments. brain (for reviews, see Refs 27, 34). One of the However, this intracellular source of Ca2+ could be of characteristics of the IBO- and Q-preferring recep- great importance for the cellular responses induced by tors that can give some clues as to their function is Qp and IBOp receptors triggering PI hydrolysis. In their pattern of activity during development. In rat particular, this increase in [Ca2+]i may stimulate the hippocampal slices, PI hydrolysis induced by EAAs activity of some Ca2+-dependent channels such as the progressively declines during postnatal development. BK (big K +) channels or a C1- channel found in many IBO stimulated basal IP formation to increase 19-fold cell types45. and 6.6-fold in slices prepared from 6- and 24-day-old In conclusion, the discovery that ionotropic (NMDA rats, respectively15. A further decrease in response and to a lesser extent, K) but also a new class of EAA was obtained when Glu was used as a stimulating receptors (comprising Q- and IBO-preferring recepagent 15. A similar decline in the Q- and Glu-mediated tors) can modify the IP/DAG pathway is likely to open PI hydrolysis was observed in forebrain synapto- up a new direction in the research into EAA brain neurosomes during postnatal development, whereas functions. in the same preparations, the K and NMDA responses remained unchanged17. One of the most Selected references exciting hypotheses would be that these receptors are 1 Watkins, J. C. and Olverman, H. J. (1987) Trends Neurosci. 10, 265-272 implicated in neuronal development and plasticity. It 2 Drejer, J. and HonorE, T. (1988) Neurosci. Lett. 87, 104-108 has been reported 35 that when axons of snail neurons 3 Nawy, S. and Copenhagen, D. R. (1987) Nature 325, 56-58 were severed, application of Glu or phorbol esters 4 Cotman, C. W., Flatman, J. A. and Ganong, A. H. (1986) (drugs known to activate PKC) induced sprouting in J. Physiol. (London) 378, 403-415 80% of one well-characterized neuron. Interestingly, 5 Eccles, J. C. and McGeer, P. L. (1979) Trends Neurosci. 2, 39-40 a role of NMDA receptors in neurite outgrowth has 6 Yatani, A., Codina, J., Brown, A. M. and Birnbaumer, L. been recently described in rat cerebellar granule cells (1987) Science 235, 207-211 in culture36, a system in which the IP response to 7 Hazeki, O. and Ui, M. (1981) J. Biol. Chem. 256, 2856-2862 NMDA is particularly potent 13. Nicoletti and his 8 Bruns, R. F., Pons, F. and Daly, J. W. (1980) Brain Res. 189, 550-555 colleagues showed that in adult rats, hippocampal 9 Novelli,A. etal. (1987) J. Neurosci. 7, 40-47 lesions increase the Q-, IBO- and Glu-mediated PI responses 37. Similar findings have been reported in 10 Berridge, M. J. (1987) Annu. Rev. Biochem. 56, 159-193 11 Downes, C. P. and Michel, R. H. (1985) in Molecular hippocampal slices of adult rat brain which received Mechanisms of Transmembrane Signalling (Cohen, P. and single or repeated hippocampal electrical stimulation Houslay, M., eds), pp. 3-56, Elsevier or electrically induced amygdala kindling~8. In all these 12 Sladeczek, F., Pin, J. P., R~casens, M., Bockaert, J. and Weiss, S. (1985) Nature 317, 717-719 experiments, neuronal plasticity is likely to occur. In 13 Nicoletti, F. etal. (1986)J. Neurosci. 6, 1905-1911 adult animals, the PI response associated with EAA 14 Nicoletti, F. etal. (1986)J. Neurochem. 46, 40--46 receptor action may play a key role in memory 15 Nicoletti, F., ladorola, M. J., Wroblewski, J. T. and Costa, E. storage. At specific pathways (especially in hippocam(1986) Proc. Natl Acad. Sci. USA 83, 1931-1935 pus), high frequency stimulation induces an increase 16 Schoepp, D. D. and Johnson, B. G. (1988) J. Neurochem. 50, 1605-1613 in synaptic efficacy (i.e. long-term potentiation: 17 R6casens, M., Sassetti, I., Nourigat, A., Sladeczek, F. and LTP)(for reviews, see Refs 39, 40). Because Bockaert, J. (1987) Eur. J. Pharmacol. 141, 87-93 hippocampal LTP can be triggered by short periods of 18 REcasens, M., Guiramand, J., Nourigat, A., Sassetti, I. and Devilliers, G. Neurochem. Int. (in press) intense synaptic activity, but lasts for hours, it has been recognized as a possible experimental model for 19 Hollingsworth, E. B. et al. (1985)J. Neurosci. 5, 2240-2253 20 Pearce, 8., Albrecht, J., Morrow, C. and Murphy, S. (1986) memory storage. Neurosci. Left. 72,335-340 An increase in intraceUular Ca 2+ concentrations is a 21 Weiss, S. etal. (1988)J. Neurochem. 50, 1425-1433 necessary step for LTP induction and roles for Ca 2+- 22 Sugiyama, H., Ito, I. and Hirono, C. (1987) Nature 325, 531-533 dependent protein kinases have been suggested (for reviews, see Refs 39, 40). However, there is 23 Krogssgaard-Larsen, P., HonorE, T., Hansen, J. J., Curtis, D. R. and Lodge, D. (1980) Nature 284, 64-66 evidence favoring the involvement of the kinase C in 24 Wroblewski, J. T., Nicoletti, F., Fadda, E. and Costa, E. (1987) LTP 41. As a matter of fact, we have shown in this Proc. Natl Acad. 5ci. USA 84, 5068-5072 TINS, VoL 11, No. 12, 1988

25 Nicoletti, F., Wroblewski, J. T. and Costa, E. (1987) J. Neurochem. 48, 967-973 26 Ascher, P. and Nowak, L. (1987) Trends Neurosci. 10, 284-288 27 Fisher, S. K. and Agranoff, B. W. (1987) Neurochemistry 48, 999-I 017 28 Kendall, D. A. and Nahorski, S. R. (1984) J. Neurochem. 42, 1388-I 394 29 Eberhard, D. A. and Holz, R. W. (1987) J. Neurochem. 49, 1634-1643 30 Monaghan, D. T. and Cotman, C. W. (1986) Proc. NatlAcad. Sci. USA 83, 7532-7536 31 Mayer, M. L., McDernott, A. B., Westbrook, G. L., Smith, S. J. and Berker, J. (1987) J. Neurosci. 17, 3230-3244 32 Baudry, M., Evans, J. and Lynch, G. (1986) Nature 319, 329-340 33 Schmidt, B. et al. (1987) Mol. Pharmacol. 32, 364-368 34 Sladeczek, F. (1987) Biochimie 69, 287-296

35 Barnes, D. M. (1986) Science 234, 1325--1326 36 Pearce, I., Cambray-Deakin, M. A. and Burgoyne, R. D. (1987) Febs. Left. 223, 143-147 37 Nicoletti, F. etal. (1987) Brain Res. 436, 103-112 38 ladorola, M. J., Nicoletti, F., Naranjo, J. R., Putman, F. and Costa, E. (1986) Brain Res. 374, 174-178 39 Collingridge, C. L. and Bliss, T. V. P. (1987) Trends Neurosci. 10, 288-293 40 Smith, S. J. (1987) Trends Neurosci. 10, 142-144 41 Hu, G. Y. etal. (1987) Nature 328, 426-429 42 Lynch, M. A., Clements, M. P., Errington, M. L. and Bliss, T. V. P. (1988) Neurosci. Left. 84, 291-296 43 Bar, P. R., Weigand, F., Lopes da Silva, F. and Gispen, W. H. (1984) Brain Res. 321,381-385 44 Ito, I., Okada, D. and Sugiyama, H. Neurosci. Left. (in press) 45 Marty, A. (1987) Trends Neurosci. 9, 373-377 46 Weiss, S. et al. (1986) Proc. Natl. Acad. Sci. USA 83, 2238-2242

Variable organization in cortical maps of the skin as an indication of the lifelong adaptive capacities of circuits in the mammalian brain J. T. W a l l

Little is understood about how integrative functions of the brain change over life. Recent studies of cortical somatosensory maps m particular genetic strains of animals and in animals that have different prenatal, postnatal, or adult histories indicate that map organization can be modified at all times between conception and death. These changes in cortical maps provide useful models for understanding changes in the integrative functions of complex brain networks throughout life. The skin contains a sheet of sensitive mechanoreceptors that is specialized for the detection of touch. This sheet has the capacity to activate a complex, widely distributed network in the brain (Fig. 1). Due to specificity in anatomical patterns of connections and functional patterns of activation, neurons at different levels of this network are integrated into map-like constructs in which the receptor sheet is somatotopically represented. This paper reviews findings indicating that structural and functional features of maps in the primary somatosensory cortex of mammals are shaped by genetic factors, and by epigenetic influences on neural adaptation capacities during subsequent prenatal, neonatal, and adult stages of life, Several conclusions are drawn from these findings that are useful for understanding the lifelong modification capacities of large networks in the mammalian brain. Genetic influences on maps The large vibrissae on the mystacial pad of rodents are arranged in an orderly pattern of rows. Each vibrissa follicle is innervated by a bundle of sensory fibers. Inputs from each bundle project through discrete central channels to layer IV of the primary somatosensory cortex, where recipient cells are arranged in 'barrels' (Fig. 2A, B) 1. This isomorphism between a cortical barrel and a peripheral follicle also TINS, Vol. 11, No. 12, 1988

reflects system function, since cells within each barrel are activated primarily by one vibrissa2. Taken together, the collection of barrels comprise an anatomical and functional map of the vibrissae. Several years ago Van der Loos and colleagues began screening mice to find individuals with abnormal arrangements of vibrissae. This screening resulted in the subsequent breeding of strains of mice with abnormal vibrissae and with cortical maps that have abnormal barrels (Fig. 2C) 3. The exact genetic mechanisms and sites for expression of these variations in cortical maps remain unclear. However, differences in the rate and degree of success in breeding abnormal follicle-barrel patterns suggest that a variety of genes are involved in producing different patterns in maps a. Although these issues require further investigation, the work to date demonstrates a genetic contribution to the production of 'normal' and 'variant' patterns of somatotopic organization in cortical maps, particularly with respect to the number and spatial arrangement of the parts of a map.

J. T. Wall is at the Department of Psychology, Vanderbilt University, Nashville, TN 37240, USA.

Maps can be modified by prenatal factors Although important, genetic factors do not act as absolute prespecifications for the organizational features of cortical maps. Maps vary significantly due to subsequent prenatal influences. For example, in normal rats the S-I cortical maps of the forepaw and hindpaw occupy neighboring positions in cortex. Similar to vibrissae maps, each forepaw and hindpaw map is comprised of regular patterns of cellular barrels and fiber terminal clusters, which are discernible with Nissl, succinic dehydrogenase (SDH), and cytochrome oxidase (CO) histochemistry. Dawson and Killackey compared the S-I cortical maps of the forepaw and hindpaw in normal rats and rats that had developed after forelimb removal on gestation day 164. They found that prenatal disruption of inputs from the forepaw significantly altered

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