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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., How NMDAR and GABA neuronal dysfunctions result in impaired social behaviour is unclear. Here, the authors show that NMDARs and gap junctions in cortical PV interneurons modulate burst firing, affecting social behaviour.

Social deficit is a major feature of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder, but its neural mechanisms remain unclear. Here, we examined neuronal discharge characteristics in the medial prefrontal cortex (mPFC) of IRSp53-mutant mice, which show social deficits, during social approach. IRSp53-mutant excitatory mPFC neurons displayed an increase in baseline neuronal firing and decreases in variability and dynamic range of firing rates and burst firing during social and non-social target approaches compared to wild-type controls. As a consequence, their firing activity was less differential between social and non-social targets. In addition, there was a decrease in the proportion of excitatory mPFC neurons encoding social information but not that of those encoding non-social information. These results suggest that insufficient neuronal activity dynamics may underlie impaired cortical encoding of social information and social behaviors in IRSp53-mutant mice.

Shank2 is an excitatory postsynaptic scaffolding protein implicated in synaptic regulation and psychiatric disorders including autism spectrum disorders. ConventionalShank2-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 deletedShank2in 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 ofShank2in mice lead to differential synaptic and behavioral abnormalities.SIGNIFICANCE STATEMENTShank2 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 reportedin vivofunctions of Shank2 mainly using globalShank2-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 conditionalShank2-mutant mice carrying theShank2deletion 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.

Netrin-G ligand-3 (NGL-3) is a postsynaptic adhesion molecule known to directly interact with the excitatory postsynaptic scaffolding protein postsynaptic density-95 (PSD-95) and trans-synaptically with leukocyte common antigen-related (LAR) family receptor tyrosine phosphatases to regulate presynaptic differentiation. Although NGL-3 has been implicated in the regulation of excitatory synapse development by in vitro studies, whether it regulates synapse development or function, or any other features of brain development and function, is not known. Here, we report that mice lacking NGL-3 (Ngl3−/− mice) show markedly suppressed normal brain development and postnatal survival and growth. A change of the genetic background of mice from pure to hybrid minimized these developmental effects but modestly suppressed N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated synaptic transmission in the hippocampus without affecting synapse development, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated basal transmission, and presynaptic release. Intriguingly, long-term depression (LTD) was near-completely abolished in Ngl3−/− mice, and the Akt/glycogen synthase kinase 3β (GSK3β) signaling pathway, known to suppress LTD, was abnormally enhanced. In addition, pharmacological inhibition of Akt, but not activation of NMDARs, normalized the suppressed LTD in Ngl3−/− mice, suggesting that Akt hyperactivity suppresses LTD. Ngl3−/− mice displayed several behavioral abnormalities, including hyperactivity, anxiolytic-like behavior, impaired spatial memory, and enhanced seizure susceptibility. Among them, the hyperactivity was rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-3 regulates brain development, Akt/GSK3β signaling, LTD, and locomotive and cognitive behaviors.

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.

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;Shank2(fl/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;Shank2(fl/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.

Although the medial prefrontal cortex (mPFC) is known to play a crucial role in rodent social behavior, little is known about mPFC neural correlates of social behavior. In the present study, we examined single-neuron activity in the mPFC of mice performing a modified version of the three-chamber test. We found that a subset of mPFC neurons elevate discharge rates when approaching a stranger mouse but not when approaching an inanimate object or an empty chamber. Our results reveal mPFC neural activity that is correlated with social approach behavior in a widely used social-interaction paradigm. These findings might be helpful for future investigations of mPFC neural processes underlying social interaction in health and disease. SIGNIFICANCE STATEMENT Although the prefrontal cortex is known to play a crucial role in rodent social behavior, little is known about prefrontal neural correlates of social behavior. This study shows that the activity of a subset of prefrontal neurons increases in association with social approach behavior during a three-chamber test—a widely used behavioral paradigm. Such responses might be a signature of prefrontal neural processes underlying social approach behavior.

Imbalances between excitation and inhibition in synaptic transmission and neural circuits have been implicated in autism spectrum disorders. Excitation and inhibition imbalances are frequently observed in animal models of autism spectrum disorders, and their correction normalizes key autistic-like phenotypes in these animals. These results suggest that excitation and inhibition imbalances may contribute to the development and maintenance of autism spectrum disorders and represent an important therapeutic target.

When subjected to stress, some individuals develop maladaptive symptoms whereas others retain normal behavior. The medial prefrontal cortex (mPFC) is known to control these adaptive responses to stress. Here, we show that mPFC neurons in the left hemisphere control stress effects on social behavior. Mice made socially avoidant by the stress of chronic social defeats showed depressed neural activity in the left mPFC. Photoactivation of these neurons reversed social avoidance and restored social activity. Despite social defeats, resilient mice with normal sociability showed normal firing rates in the left mPFC; however, photoinhibition of these neurons induced social avoidance. The same photomodulation administered to the right mPFC caused no significant effects. These results explain how stressed individuals develop maladaptive behaviors through left cortical depression, as reported in mood and anxiety disorders.