Abstract
Neuroligin-3 (Nlgn3), a neuronal adhesion protein implicated in autism spectrum disorder (ASD), is expressed at excitatory and inhibitory postsynapses and hence may regulate neuronal excitation/inhibition balance. To test this hypothesis, we recorded field excitatory postsynaptic potentials (fEPSPs) in the dentate gyrus of Nlgn3 knockout (KO) and wild-type mice. Synaptic transmission evoked by perforant path stimulation was reduced in KO mice, but coupling of the fEPSP to the population spike was increased, suggesting a compensatory change in granule cell excitability. These findings closely resemble those in neuroligin-1 (Nlgn1) KO mice and could be partially explained by the reduction in Nlgn1 levels we observed in hippocampal synaptosomes from Nlgn3 KO mice. However, unlike Nlgn1, Nlgn3 is not necessary for long-term potentiation. We conclude that while Nlgn1 and Nlgn3 have distinct functions, both are required for intact synaptic transmission in the mouse dentate gyrus. Our results indicate that interactions between neuroligins may play an important role in regulating synaptic transmission and that ASD-related neuroligin mutations may also affect the synaptic availability of other neuroligins.
Highlights
Neuroligins are transmembrane cell adhesion proteins which are localized to the postsynaptic membrane and stabilize synapses by binding to presynaptic neurexin proteins [1]
We first investigated whether Nlgn3 affects excitatory transmission in the dentate gyrus by recording field excitatory postsynaptic potentials (fEPSPs) evoked by perforant path stimulation in anesthetized WT and Nlgn3 KO mice
Since the mean fEPSP slope was reduced in Nlgn3 KO mice at nearly every stimulation intensity, we concluded that excitatory synaptic transmission from the perforant path to granule cells is impaired in Nlgn3 KO mice
Summary
Neuroligins are transmembrane cell adhesion proteins which are localized to the postsynaptic membrane and stabilize synapses by binding to presynaptic neurexin proteins [1]. Neuroligins have been implicated in synapse formation and maturation as well as neurotransmitter receptor trafficking via their interactions with scaffolding proteins such as PSD95 at excitatory postsynapses and gephyrin at inhibitory postsynapses [1]. Experiments in rodents have revealed that Nlgn is expressed only at excitatory synapses [2] and Nlgn is found mainly at inhibitory synapses [3]. Nlgn is expressed at both types of synapses [4] and forms heterodimers with Nlgn1 [5]. Nlgn has been implicated in autism spectrum disorder (ASD) in mutation screenings [6, 7]. Understanding the synaptic function of Nlgn and how it might relate to the cognitive and behavioral symptoms of ASD is a longstanding goal in neuroligin research
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