, 2008, Cuthbert et al., 2007, Ehrlich et al., 2007, Howard et al., 2010 and Migaud et al., 1998). However, other hypotheses are equally plausible. Notably, recent findings suggest that the mechanisms controlling the delivery

and maintenance of synaptic AMPARs in basal conditions and during LTP may be distinct (Adesnik et al., 2005, Ahmad et al., 2012, Jurado et al., 2013 and Sumioka et al., 2011). Synaptic cell adhesion proteins are involved in the formation, maturation, and specification of synapses (Dalva et al., 2007, Missler et al., 2012 and Siddiqui and Craig, 2011). Neuroligins (NLs) have attracted particular attention because of their synaptogenic actions when overexpressed and their genetic association with neuropsychiatric disorders (Craig IWR-1 cell line and Kang, 2007, Krueger et al., 2012 and Südhof, 2008). Although knockdown (KD) or knockout (KO) of NL1 can impair LTP, this effect may be due to the associated reduction of NMDA receptor (NMDAR)-mediated currents and spine calcium influx (Blundell et al., 2010, Chubykin et al., 2007, Kim et al., 2008 and Kwon selleck screening library et al., 2012). Recently, KD of NL1 has been reported to impair LTP in dentate gyrus granule cells and neonatal CA1 pyramidal cells independent

of an effect on NMDARs, but not at synapses on mature CA1 pyramidal cells, possibly because the LTP deficit due to NL1 KD occurs only at recently formed, immature synapses (Shipman and Nicoll, 2012). Like NLs, LRRTMs are synaptogenic in vitro, potently bind to presynaptic Nrxs, and are associated with neuropsychiatric disorders (de Wit et al., 2009, de Wit et al., 2011, Francks et al., 2007, Ko et al., 2009, Linhoff et al., 2009, Siddiqui et al., 2010 and Sousa et al., 2010). However, the functional role of LRRTMs at synapses is just beginning to be explored. LRRTMs comprise a family of four (LRRTM1–LRRTM4) homologous, Ketanserin type I transmembrane proteins with differential distribution within the brain (Laurén et al., 2003). While

the KD of LRRTM1 and/or LRRTM2 in vitro does not cause a change in synapse numbers (Ko et al., 2011), and LRRTM KDs in vitro and in vivo have yielded somewhat inconsistent results, decreases in AMPAR surface expression in vitro and AMPAR-mediated synaptic transmission in vivo have been observed (de Wit et al., 2009 and Soler-Llavina et al., 2011). Furthermore, LRRTMs may directly bind to AMPAR subunits both in vitro and in vivo (de Wit et al., 2009 and Schwenk et al., 2012). Here we used in vivo, viral-mediated KD of LRRTM1 and LRRTM2 (double knockdown, DKD) to examine the role of LRRTMs in LTP at excitatory synapses on CA1 pyramidal neurons in mouse hippocampus. LRRTM DKD blocked or dramatically impaired LTP in neonatal (postnatal days 14–18 [P14–P18]) and mature (P35–P39) CA1 pyramidal neurons, respectively.