Neurexin-Neuroligin Transsynaptic Interaction Mediates Learning-Related Synaptic Remodeling and Long-Term Facilitation in Aplysia

Abstract

SUMMARY Neurexin and neuroligin, which undergo heterophilic interactions with each other at the synapse, are mutated in some patients with autism spectrum disorder, a set of disorders characterized by deficits in social and emotional learning. We have explored the role of neurexin and neuroligin at sensory-to-motor neuron synapses of the gill-withdrawal reflex in Aplysia that undergoes sensitization, a simple form of learned fear. We find that depleting neurexin in the presynaptic sensory neuron or neuroligin in the postsynaptic motor neuron abolishes both long-term facilitation and the associated presynaptic growth induced by repeated pulses of serotonin. Moreover, introduction into the motor neuron of the R451C mutation of neuroligin-3 linked to autism spectrum disorder blocks both intermediate-term and long-term facilitation. Our results suggest that activity-dependent regulation of the neurexin-neuroligin interaction may govern trans-synaptic signaling required for the storage of long-term memory, including emotional memory that may be impaired in autism spectrum disorder.

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

“…In addition to behavioral flexibility, the autism genes in our study participate in some other cognitive processes such as learning and long-term memory (29,33,69,70). For instance, as a general translational repressor, Fmr1 interacts with Staufen and the RNAi pathway to regulate long-term memory formation.…”

New approach to capture and characterize synaptic proteome

“…kinesin | protein transport | synapse | proteome | hippocampus A number of researchers have reported specific roles of proteins that are localized to synapses, termed the "synaptic proteome," in determining synaptic function and plasticity (1)(2)(3)(4)(5)(6). Identifying the composition and dynamics of the synaptic proteome is key to understanding the remodeling of existing synapses and growth of new synapses, as well as identifying novel therapeutic targets for synaptopathies (7,8).…”

Synapse Formation in Monosynaptic Sensory–Motor Connections Is Regulated by Presynaptic Rho GTPase Cdc42

“…In contrast, NL3 is found equally at excitatory and inhibitory synapses (Budreck and Scheiffele, 2007). Moreover, overexpression of NL2 and NL3 increased both excitatory and inhibitory terminal density in vitro (Chih et al, 2005;Takahashi et al, 2011), although NL2 Ϫ / Ϫ mice show defects in only inhibitory synapses (Chubykin et al, 2007). Therefore, NL2 and/or NL3 may participate in synapse formation in sensory-motor connections in vivo.…”

“…Two DRGs from embryonic day 13.5 (E13.5) mouse embryos were cultured on coated slides and incubated with Neurobasal medium (Invitrogen) with B27 and N2 supplements (Invitrogen), L-gultamine (2 mM; Invitrogen), penicillin-streptomycin (100 U/ml; Invitrogen), and recombinant human NT-3 (20 ng/ml; R&D Systems). Half of the volume of the culture medium was changed every 3 d. 293T cells (1 ϫ 10 4 ) transfected with GFP, HA-Neurexin1␤ (Addgene, catalog #59409) HA-Neuroligin2 (Addgene, catalog #15259), or HA-Neuroligin3 (Addgene, catalog #59318) (Chih et al, 2004;Chih et al, 2006) were added to the cultured DRGs after 10 -11 d of incubation. After 2 d of coculture, DRGs were fixed with 2% PFA/PB for 20 min and immunostained with antibodies against HA (3F10; Roche), vGlut1, Pv, and Tuj1 (Covance).…”