Role for the Cadherin Family of Cell Adhesion Molecules in Synaptic Function in the Adult Hippocampus

The cadherins are a family of type I single-pass integral membrane glycoproteins that span intercellular junctions and mediate Ca2+-dependent homophilic intercellular interactions. The highly conserved cytoplasmic C termini of cadherins interact with the catenins and the cytoskeleton. The extracellular domain is composed of five repeats with the most distal repeat, especially a region containing the highly conserved His-Ala-Val (HA V) sequence, being critical for homophilic binding. I first examined the expression of cadherins, especially the neural- (N-) and epithelial- (E-) subtypes, in the adult hippocampus. In situ hybridization experiments indicated the presence of mRNAs for both N- and E- cadherins in the adult hippocampus. Immunoblot analysis revealed the expression of cadherin proteins in the hippocampal synaptosome fraction. Immunofluorescent staining indicated that cadherins and catenins are expressed at synaptic sites. I investigated the possible role of cadherins in synaptic plasticity at the CAI synapses in the adult hippocampus. Preincubation of hippocampal slices with function-blocking cadherin antibodies or HA V-containing antagonistic peptides greatly reduced long-term potentiation (LTP) whereas basal synaptic properties including input-output relations, and paired-pulse facilitation were normal. The HAV peptides inhibited LTP in a concentration- dependent and LTP induction protocol-independent manner. A decrease in the extracellular Ca2+ associated with LTP induction may increase the vulnerability of Ca2+-sensitive cadherin bonds to cadherin inhibitory reagents. In support of this hypothesis, I found that doubling of the extracellular Ca2+ abolished the inhibition of LTP by HAV peptides. Moreover, HAV peptides delivered in a lower Ca2+ solution reduced previously potentiated responses, suggesting a role for cadherins in both the induction and expression of LTP. A recombinant adenovirus containing a dominant-inhibitory cadherin cDNA was constructed. I found that hippocampal slices infected with this virus exhibited normal synaptic properties but less LTP than adjacent slices infected with an adenovirus containing a reporter gene. I also examined the effect of HAV peptides on presynaptic vesicle exocytosis in hippocampal cultures using the fluorescent membrane dye FM 1-43. HAV peptides do not affect the dye release following stimulation, suggesting cadherin function is not required for normal exocytosis. Taken together, these data suggest cadherins make important contributions to synaptic plasticity in the adult hippocampus.