Shank2 is an excitatory postsynaptic scaffolding protein implicated in synaptic regulation and psychiatric disorders including autism spectrum disorders. Conventional Shank2-mutant (Shank2-/-) mice display several autistic-like behaviors, including social deficits, repetitive behaviors, hyperactivity, and anxiety-like behaviors. However, cell-type-specific contributions to these behaviors have remained largely unclear. Here, we deleted Shank2 in specific cell types and found that male mice lacking Shank2 in excitatory neurons (CaMKII-Cre;Shank2fl/fl) show social interaction deficits and mild social communication deficits, hyperactivity, and anxiety-like behaviors. In particular, male mice lacking Shank2 in GABAergic inhibitory neurons (Viaat-Cre;Shank2fl/fl) display social communication deficits, repetitive self-grooming, and mild hyperactivity. These behavioral changes were associated with distinct changes in hippocampal and striatal synaptic transmission in the two mouse lines. These results indicate that cell-type-specific deletions of Shank2 in mice lead to differential synaptic and behavioral abnormalities.SIGNIFICANCE STATEMENT Shank2 is an abundant excitatory postsynaptic scaffolding protein implicated in the regulation of excitatory synapses and diverse psychiatric disorders including autism spectrum disorders. Previous studies have reported in vivo functions of Shank2 mainly using global Shank2-null mice, but it remains largely unclear how individual cell types contribute to Shank2-dependent regulation of neuronal synapses and behaviors. Here, we have characterized conditional Shank2-mutant mice carrying the Shank2 deletion in excitatory and inhibitory neurons. These mouse lines display distinct alterations of synaptic transmission in the hippocampus and striatum that are associated with differential behavioral abnormalities in social, repetitive, locomotor, and anxiety-like domains.

NMDA receptor (NMDAR) and GABA neuronal dysfunctions are observed in animal models of autism spectrum disorders, but how these dysfunctions impair social cognition and behavior remains unclear. We report here that NMDARs in cortical parvalbumin (Pv)-positive interneurons cooperate with gap junctions to promote high-frequency (>80 Hz) Pv neuronal burst firing and social cognition. Shank2-/- mice, displaying improved sociability upon NMDAR activation, show impaired cortical social representation and inhibitory neuronal burst firing. Cortical Shank2-/- Pv neurons show decreased NMDAR activity, which suppresses the cooperation between NMDARs and gap junctions (GJs) for normal burst firing. Shank2-/- Pv neurons show compensatory increases in GJ activity that are not sufficient for social rescue. However, optogenetic boosting of Pv neuronal bursts, requiring GJs, rescues cortical social cognition in Shank2-/- mice, similar to the NMDAR-dependent social rescue. Therefore, NMDARs and gap junctions cooperate to promote cortical Pv neuronal bursts and social cognition.

BACKGROUND: Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. METHODS: We used Shank2-/- mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. RESULTS: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2-/- mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype-NMDAR hyperfunction-at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7-P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56). CONCLUSIONS: Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2-/- mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages.