In humans, four major genes encode for a family of proteins termed neuroligins. These single-pass transmembrane proteins are found at postsynaptic sites, where they support the formation and maintenance of synapses through both intracellular, as well as trans-synaptic interactions ( Washbourne et al., 2004). A cursory look at the neuroligins reveals high sequence and structural

homology and a shared major binding partner in presynaptic neurexin ( Ichtchenko et al., 1996). Indeed, this similarity is borne Anti-cancer Compound Library in vitro out functionally, as all of the neuroligins promote the formation and maintenance of synapses ( Chih et al., 2005; Levinson et al., 2005). However, some notable differences have begun to emerge between the neuroligins, suggesting divergent roles for the individual members of this

family. Most dramatically, differences exist between neuroligin subtypes http://www.selleckchem.com/products/Adriamycin.html with regard to expression patterns at excitatory and inhibitory synapses, with neuroligin 1 (NLGN1) and neuroligin 3 (NLGN3) found at excitatory synapses and neuroligin 2 (NLGN2) and NLGN3 found at inhibitory synapses (Budreck and Scheiffele, 2007; Song et al., 1999; Varoqueaux et al., 2004). However, beyond the broad excitatory/inhibitory divide, subtle differences exist specifically between second the two major neuroligin subtypes found endogenously at excitatory synapses, NLGN1 and NLGN3. Notably, NLGN1 knockout animals have been shown to have deficits in memory (Blundell et al., 2010; Kim et al., 2008), while NLGN3 has been more strongly linked to autism and impairments in social behavior (Radyushkin

et al., 2009). Yet, little has been done to directly compare the physiological roles of these two proteins. In the present study, we explored for possible functional differences between NLGN1 and NLGN3. Using a variety of in vivo and in vitro techniques combining both knockdown and molecular replacement of the subtypes, we present differences in the physiological roles of these two proteins, most strikingly with respect to plasticity. Specifically, we find that NLGN1 has a clear role in the support of LTP in the hippocampus—in young CA1, but extending into adulthood in the dentate gyrus—a role that is not shared by NLGN3. We provide the first molecular dissection of the physiological differences between these neuroligin subtypes at excitatory synapses and find that the unique functions of NLGN1, both the potency of its synaptogenic phenotype and its role in LTP, depend on the inclusion of the B splice insertion site in its extracellular domain.