Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention. Zinc (Zn) is a nutritional factor implicated in ASDs, but evidence for a strong association and linking mechanism is largely lacking. Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation.

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Nav1.2, a voltage-gated sodium channel subunit encoded by the Scn2a gene, has been implicated in various brain disorders, including epilepsy, autism spectrum disorder, intellectual disability, and schizophrenia. Nav1.2 is known to regulate the generation of action potentials in the axon initial segment and their propagation along axonal pathways. Nav1.2 also regulates synaptic integration and plasticity by promoting back-propagation of action potentials to dendrites, but whether Nav1.2 deletion in mice affects neuronal excitability, synaptic transmission, synaptic plasticity, and/or disease-related animal behaviors remains largely unclear. Here, we report that mice heterozygous for the Scn2a gene ( Scn2a +/- mice) show decreased neuronal excitability and suppressed excitatory synaptic transmission in the presence of network activity in the hippocampus. In addition, Scn2a +/- mice show suppressed hippocampal long-term potentiation (LTP) in association with impaired spatial learning and memory, but show largely normal locomotor activity, anxiety-like behavior, social interaction, repetitive behavior, and whole-brain excitation. These results suggest that Nav1.2 regulates hippocampal neuronal excitability, excitatory synaptic drive, LTP, and spatial learning and memory in mice.

Extensive evidence links Glutamate receptor, ionotropic, NMDA2B (GRIN2B), encoding the GluN2B/NR2B subunit of N-methyl-D-aspartate receptors (NMDARs), with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), but the underlying mechanisms remain unclear. In addition, it remains unknown whether mutations in GluN2B, which starts to be expressed early in development, induces early pathophysiology that can be corrected by early treatments for long-lasting effects. We generated and characterized Grin2b-mutant mice that carry a heterozygous, ASD-risk C456Y mutation (Grin2b +/C456Y). In Grin2b +/C456Y mice, GluN2B protein levels were strongly reduced in association with decreased hippocampal NMDAR currents and NMDAR-dependent long-term depression (LTD) but unaltered long-term potentiation, indicative of mutation-induced protein degradation and LTD sensitivity. Behaviorally, Grin2b +/C456Y mice showed normal social interaction but exhibited abnormal anxiolytic-like behavior. Importantly, early, but not late, treatment of young Grin2b +/C456Y mice with the NMDAR agonist D-cycloserine rescued NMDAR currents and LTD in juvenile mice and improved anxiolytic-like behavior in adult mice. Therefore, GluN2B-C456Y haploinsufficiency decreases GluN2B protein levels, NMDAR-dependent LTD, and anxiety-like behavior, and early activation of NMDAR function has long-lasting effects on adult mouse behavior.