Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1

Abstract

Select adhesion proteins control the development of synapses and modulate their structural and functional properties. Despite these important roles, the extent to which different synapse-organizing mechanisms act across brain regions to establish connectivity and regulate network properties is incompletely understood. Further, their functional roles in different neuronal populations remain to be defined. Here, we applied diffusion tensor imaging (DTI), a modality of magnetic resonance imaging (MRI), to map connectivity changes in knock-out (KO) mice lacking the synaptogenic cell adhesion protein SynCAM 1. This identified reduced fractional anisotropy in the hippocampal CA3 area in absence of SynCAM 1. In agreement, mossy fiber refinement in CA3 was impaired in SynCAM 1 KO mice. Mossy fibers make excitatory inputs onto postsynaptic specializations of CA3 pyramidal neurons termed thorny excrescences and these structures were smaller in the absence of SynCAM 1. However, the most prevalent targets of mossy fibers are GABAergic interneurons and SynCAM 1 loss unexpectedly reduced the number of excitatory terminals onto parvalbumin (PV)-positive interneurons in CA3. SynCAM 1 KO mice additionally exhibited lower postsynaptic GluA1 expression in these PV-positive interneurons. These synaptic imbalances in SynCAM 1 KO mice resulted in CA3 disinhibition, in agreement with reduced feedforward inhibition in this network in the absence of SynCAM 1-dependent excitatory drive onto interneurons. In turn, mice lacking SynCAM 1 were impaired in memory tasks involving CA3. Our results support that SynCAM 1 modulates excitatory mossy fiber inputs onto both interneurons and principal neurons in the hippocampal CA3 area to balance network excitability.

SynCAMs – From axon guidance to neurodevelopmental disorders

“…The role of SynCAM1 and SynCAM2 in synaptogenesis has been extensively studied, as this feature was the basis for their discovery (Fogel et al, 2007;Stagi et al, 2010;Robbins et al, 2010;Park et al, 2016). Confirmation of the role of SynCAMs in synapse formation came from heterologous co-culture assays (Biederer and Scheiffele, 2007;see above) showing that overexpression of SynCAM1 in non-neuronal cells induced functional presynaptic terminal differentiation in cocultured hippocampal neurons (Biederer et al, 2002;Sara et al, 2005).…”

Transcellular Nanoalignment of Synaptic Function

“…In terms of physiological maturation, neurexins are critical synaptic organizers as first shown in vivo by the result that α-neurexin loss impairs evoked neurotransmission (Missler et al, 2003). Additional evidence for instructive roles of trans-synaptic organizers in synapse development comes from studies of another class of postsynaptic neurexin ligands called LRRTM proteins (de Wit and Ghosh, 2016), LAR phosphotyrosine phosphatases that signal on the presynaptic side (Takahashi and Craig, 2013), and SynCAM 1, which is preferentially postsynaptic and required and sufficient to control the number of excitatory synapses in vivo (Park et al, 2016; Korber and Stein, 2016; Robbins et al, 2010). The subsynaptic functions of these and other adhesion molecules could include localization or retention of pre- and post-synaptic nanodomains at developing and mature synapses, altering the geometry of the cleft and hence the diffusion of neurotransmitters, or modulating presynaptic Ca channel function (Freche et al, 2011; Glebov et al, 2016; Tong et al, 2017; Wahl et al, 1996).…”

Stability in the Face of Change: Lifelong Experience-Dependent Plasticity in the Sensory Cortex

“…While the limited and transient restoration of developmental plasticity in the mature cortex may be beneficial for reestablishing the correct circuit architecture after brain injury and in numerous disorders characterized by aberrant connectivity (Levelt and Hübener, 2012;Hübener and Bonhoeffer, 2014;, prolonging critical periods into adulthood is detrimental. Mice lacking structural brakes on plasticity, such as ECM, myelin-associated receptor NogoR, the cell adhesion molecule 1, as well as adult mice transplanted with embryonic interneurons, show deprivation-induced plasticity well into adulthood, but also display impairments in associative conditioning learning paradigms (Gogolla et al, 2009;Akbik et al, 2013;Park et al, 2016;Yang et al, 2016;Banerjee et al, 2017;Thompson et al, 2018). This indicates that the tapering of developmental plasticity is a requirement for the transition to adult forms of learning.…”