Abstract
Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively.
Highlights
Proper balance between inhibitory and excitatory connections is important for proper functioning of neuronal circuits (Mackowiak et al, 2014; Bang and Owczarek, 2013)
Further analysis via expression of chimeric NLGN2/3 constructs on a reduced endogenous NLGN background revealed that this difference between NLGN2 and 3 function at inhibitory synapses is due to differences within a domain in the extracellular region corresponding to a site important for neurexin binding, as well as a proximal uncharacterized region
While this result seemed to suggest that the intracellular region is not important, our results clearly show that, the intracellular region of any NLGN is sufficient for function at inhibitory synapses, if paired with the extracellular region of NLGN2, a c-tail is very much required
Summary
Proper balance between inhibitory and excitatory connections is important for proper functioning of neuronal circuits (Mackowiak et al, 2014; Bang and Owczarek, 2013). Cell adhesion molecules have a critical role in coordinating the apposition of presynaptic terminals with postsynaptic sites of differentiation (Washbourne et al, 2004; Yamagata et al, 2003). While much work has been done to determine the molecular organization of cell adhesion molecules at excitatory synapses, less is known about how these components are organized at inhibitory synapses. Neuroligins are a family of postsynaptic cell adhesion molecules that interact trans-synaptically with their corresponding presynaptic neurexin binding partners to mediate proper synaptic function (Sudhof, 2008; Chih et al, 2005). One notable difference between NLGN2 and 3 resides in the extracellular region at splice site A which has previously been proposed to affect NLGN binding to its presynaptic neurexin partner (Ichtchenko et al, 1996; Chih et al, 2006)
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