Role of Cell Adhesion Molecules in Synaptic Plasticity and Memory

cbb506.qxd 10/27/1999 7:57 AM Page 549 549 The role of cell adhesion molecules in synaptic plasticity and memory Sachiko Murase and Erin M Schuman∗ Studies in the past few years suggest that cell adhesion roles in the activity-dependent rearrangement of synaptic molecules may play signaling as well as structural roles at adult structures in the adult brain. In this review, we highlight synapses during plasticity. The observation that many adhesion recent studies implicating cell adhesion molecules as molecules are expressed both pre-synaptically and post- mediators of synaptic and behavioral plasticity. The possi- synaptically raises the possibility that information about ble mechanism(s) by which these molecules participate in synaptic activity might simultaneously be communicated to plasticity is also discussed. both sides of the synapse, circumventing the need for distinct anterograde and retrograde messengers. Involvement of cell adhesion molecules in synaptic plasticity and learning Addresses Synapses, the points of contact between neurons, undergo Howard Hughes Medical Institute, Division of Biology, California dynamic changes in their strength, enduring from minutes Institute of Technology, 1200 East California Boulevard, Pasadena, to hours to days. The presence of adhesion molecules in or CA 91125, USA near the synaptic cleft raises the possibility that, in addi- ∗e-mail: [email protected] tion to serving as recognition molecules for Current Opinion in Cell Biology 1999, 11:549–553 synaptogenesis, they may participate in initiating and 0955-0674/99/$ — see front matter © 1999 Elsevier Science Ltd. maintaining synaptic changes. One prominent form of All rights reserved. synaptic change exhibited by many different synapses is long-term potentiation (LTP), an enduring enhancement Abbreviations apCAM Aplysia NCAM homolog of excitatory synaptic transmission that occurs following HAV His–Ala–Val brief episodes of synaptic activity. Since it was first discov- IAP integrin-associated protein ered in the hippocampus — a brain structure implicated in Ig immunoglobulin memory formation — this type of synaptic plasticity has LTP long-term potentiation been intensively studied as a potential model for how MAPK mitogen-activated protein kinase NCAM neural cell adhesion molecule information is stored during animal learning. Over the past RGD Arg–Gly–Asp few years, several studies have shown that adhesion molecules may participate in both synaptic changes, such as Introduction LTP, and behavioral changes, such as learning. During brain development, growing axons must recognize and establish connections with the appropriate postsynap- Integrin superfamily tic target neurons in order to establish the functional Integrins are a family of proteins that interact with extra- neural circuits that mediate animal behavior. Once these cellular matrix proteins. A highly conserved five amino synaptic circuits are established, they can undergo modifi- acid residue sequence, including Arg–Gly–Asp (RGD), is cations including the addition or deletion of synapses, or found in most of the ligands of integrins; this sequence is the alteration of pre-existing synapses. This capacity for known to be critical for ligand binding to integrins. change — synaptic plasticity — represents the nervous Blocking integrin function with a peptide containing the system’s ability to encode and represent changes in the RGD sequence causes a decay of LTP in the CA1 region environment, that is the ability to learn and remember. of adult rat hippocampus [12]. The peptide-mediated inhi- bition of LTP was time-dependent: the application of the Adhesion molecules are known to participate in target antagonist peptides 10 minutes, but not 25 minutes, after recognition and stabilization during synaptogenesis. They LTP induction was effective in blocking LTP, suggesting are required for axonal development from the initial induc- that integrin function is required for a very early stage of tion of outgrowth [1] to the guidance to the target [2,3]. In LTP stabilization [13]. Integrins also participate in a form the chicken optic tectum, for example, the lamina-specific of short-term synaptic plasticity termed stretch-induced expression patterns of cell adhesion molecules [4] regulate enhancement of neurotransmitter release at frog motor the connectivity of ingrowing fibers [5]. In Drosophila, nerve terminals [14]. At this synapse, a transient force Fasciclin II, an immunoglobulin (Ig) superfamily protein is applied to the muscle results in an increase in the fre- localized at synapses and controls the number of boutons quency of miniature end-plate potentials. The application and the structure of the neuromuscular junction [6–8]. of RGD peptides can block the stretch-induced enhance- Studies such as these highlight the importance of adhesion ment of synaptic strength. molecules in target recognition and synaptogenesis. In Drosophila, the locus linked to a mutant called Volado, Because the expression of many cell adhesion molecules which displays impaired olfactory associative memory, was persists in adulthood [9,10••,11], they may play analogous found to encode two isoforms of a new type of integrin, cbb506.qxd 10/27/1999 7:57 AM Page 550 550 Cell-to-cell contact and extracellular matrix Figure 1 ed before a morphological alteration can be ruled out. Nevertheless, these results suggest the possibility that integrin signaling, rather than integrin structural support, is (a) required for memory in Drosophila. 250 Related to the above point, an integrin-associated protein 200 (IAP), which was recently found to be involved in tyrosine AHAVD kinase signaling [16], appears to influence memory performance in rats [17•]. Differential display was used to 150 compare hippocampal cDNAs from rats that perform poor- ly versus those that perform well on an inhibitory avoidance learning task [17•]. Three cDNAs correspond- 100 ing to splice variants of IAP exhibited elevated expression in the hippocampus of the rats with a good memory. AHAVD 50 Injection of antisense oligonucleotides to IAP into the hip- -15 0 15 30 45 60 pocampus impaired memory retention and also reduced (b) the magnitude of LTP recorded in vivo. Future studies are 350 5 mM Ca2+ needed to determine the subcellular localization of IAP(s) in the hippocampus and whether IAP works together with 300 integrins during plasticity or independently. fEPSP INITIAL SLOPE (mean percent of baseline) 250 Immunoglobulin superfamily 200 Some studies have suggested that the neuronal Ig super- 0.2 mM AHAVD family is involved in both synaptogenesis and synaptic 150 plasticity. Mice with a targeted deletion of the NCAM (neural cell adhesion molecule) gene showed an impair- 100 ment of axonal growth and synaptogenesis in the hippocampal mossy fiber axon system [18,19]. (Mossy 0.2 mM AHAVD 50 fibers are usually restricted to the proximal dendrites of -15 0 15 30 45 60 CA3 cells.) Axons in the mutant CA3 hippocampus are no Time (min) Current Opinion in Cell Biology longer fasciculated and mossy fiber presynaptic terminals are present ectopically in the CA3 cell body layer and Peptides containing the sequence HAV (in the single letter code for amino acids) perturb the induction of LTP but not the maintenance of throughout the CA3 region. Despite these morphological LTP. (a) Superimposed ensemble averages from two-pathway abnormalities, basal synaptic transmission and short-term experiments conducted in the same slices. Bath application of an synaptic plasticity were normal in the mutant mice [19]. AHAVD (in the single letter code for amino acids) peptide for LTP however, was abolished in these mice in both area 20 minutes prior to tetanus significantly reduces LTP in pathway 2 CA3 [19] and CA1 [20]. These observations are supported (open triangles) whereas application of the same peptide 30 minutes after LTP induction in pathway 1 has no significant effect on established by an earlier study showing that application of function- potentiation (black triangles). (b) Ensemble averages for two-pathway blocking antibodies to either NCAM or L1, an Ig family experiments in which the HAV peptide was applied either 30 minutes member, were found to inhibit LTP induction in area CA1 before (open triangles) or after (black triangles) LTP induction by [21]. When LTP was examined in a different NCAM tetanus in an altered artificial cerebrospinal fluid containing 5.0 mM Ca2+. Individual superimposed representative electrophysiological knockout mouse, however, a different result was obtained traces are shown for each experimental group 10 minutes before and [22•]. LTP in area CA1 was indistinguishable in homozy- 50–60 minutes after LTP induction. Scale bar is 0.5 mV/20 msec. gous, heterozygous and wild-type animals, despite the fact •• Reprinted with permission from [10 ]. that the knockout animals share the same morphological abnormalities in area CA3 reported in the other NCAM knockout [18,19]. Strain differences may account for this α-integrin [15••]. The Volado gene product is expressed in discrepancy, as the age of the animals as well as the stimu- the mushroom body, an area known to be important for lation parameters were similar in the two studies. learning in insects. Conditional expression of the wild-type Volado transgene in the Volado mutants can rescue the In addition, NCAM knockout mice exhibited deficits in memory impairment, suggesting that the lack of integrin performance on the Morris water maze, a spatial memory function is indeed the

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