Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals

Abstract

Neuroligin-1 is a potent trigger for the de novo formation of synaptic connections, and it has recently been suggested that it is required for the maturation of functionally competent excitatory synapses. Despite evidence for the role of neuroligin-1 in specifying excitatory synapses, the underlying molecular mechanisms and physiological consequences that neuroligin-1 may have at mature synapses of normal adult animals remain unknown. By silencing endogenous neuroligin-1 acutely in the amygdala of live behaving animals, we have found that neuroligin-1 is required for the storage of associative fear memory. Subsequent cellular physiological studies showed that suppression of neuroligin-1 reduces NMDA receptor-mediated currents and prevents the expression of long-term potentiation without affecting basal synaptic connectivity at the thalamo-amygdala pathway. These results indicate that persistent expression of neuroligin-1 is required for the maintenance of NMDAR-mediated synaptic transmission, which enables normal development of synaptic plasticity and long-term memory in the amygdala of adult animals.synaptic plasticity ͉ neuroligin ͉ autism S everal studies have found that synaptically localized cell adhesion molecules not only trigger synapse formation but also play a major role in regulating both basal synaptic transmission and synaptic plasticity (1, 2). Among them, neurexins and neuroligins (NLs), which undergo a heterophilic interaction with each other, have emerged as important organizers of de novo synapse formation (3). Moreover, modifying the interaction of neuroligin-1 and PSD-95 alters the balance of neuronal excitation and inhibition required for normal brain function (4). The indispensable role of neuroligins for proper neuronal connectivity is further supported by the genetic linkage of neuroligin mutations with autism, a disease that is thought to be a disorder in social cognition that critically involves the amygdala (5, 6).Because neuroligins are present both during development and throughout adulthood (7,8), it is likely that neuroligins play roles other than that of an inducer of synaptogenesis in the adult brain. Indeed, a recent study of knockout (KO) mice deficient in neuroligin-1 demonstrated that neuroligin-1 regulates excitatory synaptic responses (9). Although neuroligin-1 has been suggested to be essential for maintaining normal N-methyl-D-aspartate (NMDA)-type glutamate receptor-mediated currents (9), the underlying mechanism and its physiological consequence remain to be identified. Furthermore, because the regulation of NMDA receptor (NMDAR) is critical for long-term synaptic modification (10), alterations of NMDAR-dependent currents regulated by neuroligin-1 are likely to have effects on synaptic plasticity and long-term memory in adult animals.To address the functional role of neuroligin-1 at existing mature synapses, we used virus-mediated RNA interference to deplete endogenous neuroligin-1 in the lateral nucleus of the amygdala (LA) of adult animals. We investigated the actions...

The neurexin ligands, neuroligins and leucine-rich repeat transmembrane proteins, perform convergent and divergent synaptic functions in vivo

“…Our results suggest that, at mature synapses, NLs and LRRTMs subserve different functions than at developing synapses. NL1 is essential for the regulation of NMDAR-mediated synaptic responses, consistent with findings based on recordings from hippocampal pyramidal neurons in slices prepared from NL1 KO mice (10) and amygdala principle neurons on acute KD of NL1 (14,15). We have extended these results in two ways.…”

“…4B) (NL1 KO = 0.76 ± 0.05 of WT). This observation is consistent with previous results and has been attributed to a decrease in the number of synaptic NMDARs (10,14,15). NL3 KD in the NL1 KO cells did not further decrease the NMDAR/AMPAR ratio, suggesting that NL1 is the predominant NL for maintaining NMDAR-mediated transmission at mature excitatory CA1 synapses (Fig.…”

The role of cell adhesion molecules (CAMs) in defining synapse-specific function and plasticity

“…In adult mice, knock-out of neuroligin-1 causes deficits in memory and learning-related synaptic plasticity (Kim et al, 2008;Blundell et al, 2010), whereas knock-out of neuroligin-3 induces autism and impairment in social behavior without memory deficit (Radyushkin et al, 2009). Supporting this, neuroligin-1 but not neuroligin-3 is required for the induction of long-term potentiation, and this subtype-specific synaptic role is dependent on its extracellular domain of neuroligin-1 (Shipman & Nicoll, 2012).…”

“…However, genetic deletion of neuroligins did not alter the normal synapse density and synaptic ultrastructure in vivo (Varoqueaux et al, 2006;Kim et al, 2008;Blundell et al, 2010). These contradicting results have suggested that neuroligins are not required for the initial synaptic formation but for the maturation of the pre-existing synapses or normal synaptic function.…”

PICK1 Mediates Synaptic Recruitment of AMPA Receptors at Neurexin-Induced Postsynaptic Sites

“…In mice featuring triple knockouts of neuroligin or ␣-neurexin genes, severe defects in synaptic transmission were observed (Missler et al, 2003;Varoqueaux et al, 2006). Altered expression levels of neuroligins led to learning defects or impaired social interactions in mice (Hines et al, 2008;Kim et al, 2008b). Mutations of human neurexin and neuroligin genes were found to be associated with autism spectrum disorders and mental retardation (Jamain et al, 2003;Laumonnier et al, 2004;Feng et al, 2006;Arking et al, 2008;Kim et al, 2008a;Yan et al, 2008a,b).…”