Heterophilic Type II Cadherins Are Required for High-Magnitude Synaptic Potentiation in the Hippocampus

Abstract

Summary Hippocampal CA3 neurons form synapses with CA1 neurons in two layers, stratum oriens (SO) and stratum radiatum (SR). Each layer develops unique synaptic properties but molecular mechanisms that mediate these differences are unknown. Here, we show SO synapses normally have significantly more mushroom spines and higher magnitude long-term potentiation (LTP) than SR synapses. Further, we discovered these differences require the Type II classic cadherins, cadherins-6, 9, and 10. Though cadherins typically function via trans-cellular homophilic interactions, our results suggest presynaptic cadherin-9 binds postsynaptic cadherins-6 and 10 to regulate mushroom spine density and high magnitude LTP in the SO layer. Loss of these cadherins has no effect on the lower magnitude LTP typically observed in the SR layer, demonstrating that cadherins-6, 9, and 10 are gatekeepers for high magnitude LTP. Thus, Type II cadherins may uniquely contribute to the specificity and strength of synaptic changes associated with learning and memory.

Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins

“…The limited heterophilic responses observed between d2-protocadherins produced far lower responses than homophilic binding, and thus their physiological significance is less clear. Heterophilic interactions, commonly found for protein families that function primarily in adhesion, can play a role at boundaries between different cell types sharing a single family member (Basu et al, 2018;Brasch et al, 2018;Generous et al, 2019;Labernadie et al, 2017;Togashi et al, 2011;Volk et al, 1987), or in refining celllevel interaction specificity when co-expressed (Carrillo et al, 2015;Cosmanescu et al, 2018;Patel et al, 2006;Xu et al, 2018). As described above, d-protocadherins are often coexpressed in the same cell (Etzrodt et al, 2009), and effects of d-protocadherin co-expression on cell-interaction specificity have been demonstrated in cell aggregation experiments (Bisogni et al, 2018;Pederick et al, 2018).…”

Calsyntenin-3 directly interacts with neurexins to orchestrate excitatory synapse development in the hippocampus

“…Although it is possible that other unidentified proteins could also bind to Clstn3 cadherin domains, it is likely that presynaptic neurexins and postsynaptic Clstn3 control the properties of excitatory synapse development in specific Schaffercollateral projections within the SR layer. A recent paper highlighted the fact that the distinctive features of two different Schaffer-collateral projections differentially regulate mushroom spine density and high-magnitude LTP in the SO layer, organized by heterophilic type II cadherins (Basu et al, 2017). Moreover, Nrxn genes show differential, but overlapping, isoform-and region-dependent expression in different classes of neurons, and undergo highly distinctive, cell type-specific alternative splicing (Nguyen et al, 2016;Ullrich et al, 1995).…”

Kirrel3-mediated synapse formation is attenuated by disease-associated missense variants

“…Neuron cultures were prepared as previously described (Martin et al, 2015; Basu et al, 2017). Briefly, rat cortical astrocytes were plated to glass coverslips coated with 0.03mg/ml (~7.5μg/cm 2 ) of PureCol (Advanced Biomatrix, Cat# 5005) and grown to confluence in glia feeding media: MEM (GIBCO Cat# 11090-081) supplemented with 10% FBS (Atlas Biologicals Cat# FP-0500-A), 30mM glucose, 1x penicillin-streptomycin solution (GIBCO Cat# 15070-063).…”

“…The integrated density of the chicken-anti-FLAG (extracellular) signal was quantified per cell and divided by the integrated density of the mouse-anti-FLAG (intracellular) signal to determine the extracellular/intracellular ratio. General culture conditions and solutions for CHO cells were previously described (Martin et al, 2015; Basu et al, 2017). Analysis was performed blind to condition.…”

“…The aggregation assay was performed as previously described (Martin et al, 2015; Basu et al, 2017). CHO cells were transfected with mCherry-pBOS, wild-type mCherry-2A-FLAG-Kirrel3-pBOS, or the missense equivalents.…”