, 1992 and Ushkaryov and Südhof, 1993). The cytoplasmic domain of both neurexin and neuroligin contains PDZ-binding motifs that can recruit signaling molecules thought to mediate differentiation of the presynaptic and the postsynaptic compartment, respectively. Indeed, in vitro, neurexin and neuroligin promote synapse formation by inducing post- and presynaptic differentiation, by interacting with each other (Scheiffele et al., 2000, Graf et al., 2004 and Chih et al., 2005). However, in vivo studies using gene ablation of neurexins or neuroligins in mice found no obvious changes check details in synapse number,

leading to the suggestion that in vivo neurexin and neuroligin affect synaptic remodeling and maturation rather than initial synapse formation (Missler et al., 2003 and Varoqueaux et al., 2006; reviewed in Südhof, 2008). The finding that chronic inhibition of NMDA receptors suppresses the synaptogenic activity of neuroligin-1 Rigosertib cell line in vitro further supports the idea that neuroligin contributes to the activity-dependent modification of developing neural circuits (Chubykin et al., 2007). In light of these experimental results, it is particularly interesting that human neuroligin (NLG-3 and NLG-4) and neurexin (NRX-1α) have been linked to autism spectrum disorder (ASD: Jamain et al., 2003, Laumonnier et al., 2004, Autism Genome Project Consortium, 2007 and Kim et al., 2008a). Since children with ASD often develop normally

up to a point and only then regress in their social and emotional development, ASD is thought not to affect initial synapse formation but rather the synaptic remodeling that accompanies

maturation of the nervous Rolziracetam system and the subsequent stabilization of these synaptic connections (Zoghbi, 2003). The postulated role of neurexin and neuroligin in synaptic remodeling and maturation and in the pathogenesis of ASD makes it interesting to explore their role in emotional learning and memory. As a first step in this direction, we examined the role of neuroligin-1 in mammals and found it to be important for memory of learned fear and for associated LTP at mature neural circuits in the amygdala (Kim et al., 2008b). More recently, neuroligin-1 has also been found to contribute to hippocampus-dependent spatial memory (Dahlhaus et al., 2010 and Blundell et al., 2010). However, there have been no detailed molecular studies thus far of how neuroligin contributes to the different stages of emotional memory formation or how it contributes to the learning-induced structural remodeling that leads to the growth of new synaptic connections associated with the storage of long-term emotional memory. Moreover, although neurexin-1α knockout mice have enhanced motor learning despite a defect in excitatory neurotransmission (Etherton et al., 2009), there are also no studies examining the role of neurexins in learning-related synaptic plasticity.