Over the past 3 decades, the prevalence of autism spectrum disorder (ASD) has increased globally from 20 to 28 million cases making ASD the fastest-growing developmental disability in the world. Neurexins are a family of presynaptic cell adhesion molecules that have been increasingly implicated in ASD, as evidenced by genetic mutations in the clinical population. Neurexins function as context-dependent specifiers of synapse properties and critical modulators in maintaining the balance between excitatory and inhibitory transmission (E/I balance). Disrupted E/I balance has long been established as a hallmark of ASD making neurexins excellent starting points for understanding the etiology of ASD. Herein we review neurexin mutations that have been discovered in ASD patients. Further, we discuss distinct synaptic mechanisms underlying the aberrant neurotransmission and behavioral deficits observed in different neurexin mouse models, with focus on recent discoveries from the previously overlooked neurexin-2 gene (Nrxn2 in mice and NRXN2 in humans). Hence, the aim of this review is to provide a summary of new synaptic insights into the molecular underpinnings of ASD.

Neurexins (Nrxns) have been extensively studied for their role in synapse organization and have been linked to many neuropsychiatric disorders, including autism spectrum disorder (ASD), and epilepsy. However, no studies have provided direct evidence that Nrxns may be the key regulator in the shared pathogenesis of these conditions largely due to complexities among Nrxns and their non-canonical functions in different synapses. Recent studies identified NRXN2 mutations in ASD and epilepsy, but little is known about Nrxn2’s role in a circuit-specific manner. Here, we report that conditional deletion of Nrxn2 from the hippocampus and cortex (Nrxn2 cKO) results in behavioral abnormalities, including reduced social preference and increased nestlet shredding behavior. Electrophysiological recordings identified an overall increase in hippocampal CA3→CA1 network activity in Nrxn2 cKO mice. Using intracranial electroencephalogram recordings, we observed unprovoked spontaneous reoccurring electrographic and behavioral seizures in Nrxn2 cKO mice. This study provides the first evidence that conditional deletion of Nrxn2 induces increased network activity that manifests into spontaneous recurrent seizures and behavioral impairments.

Early life adversity (ELA) is a major health burden in the United States, with 62% of adults reporting at least one adverse childhood experience. These experiences during critical stages of brain development can perturb the development of neural circuits that mediate sensory cue processing and behavioral regulation. Recent studies have reported that ELA impaired the maturation of dendritic spines on neurons in the dorsolateral striatum (DLS) but not in the dorsomedial striatum (DMS). The DMS and DLS are part of two distinct corticostriatal circuits that have been extensively implicated in behavioral flexibility by regulating and integrating action selection with the reward value of those actions. To date, no studies have investigated the multifaceted effects of ELA on aspects of behavioral flexibility that require alternating between different action selection strategies or higher-order cognitive processes, and the underlying synaptic transmission in corticostriatal circuitries. To address this, we employed whole-cell patch-clamp electrophysiology to assess the effects of ELA on synaptic transmission in the DMS and DLS. We also investigated the effects of ELA on the ability to update action control in response to outcome devaluation in an instrumental learning paradigm and reversal of action-outcome contingency in a water T-maze paradigm. At the circuit level, ELA decreased corticostriatal glutamate transmission in male but not in female mice. Interestingly, in DMS, glutamate transmission is decreased in male ELA mice, but increased in female ELA mice. ELA impaired the ability to update action control in response to reward devaluation in a context that promotes goal-directedness in male mice and induced deficits in reversal learning. Overall, our findings demonstrate the sex- and region-dependent effects of ELA on behavioral flexibility and underlying corticostriatal glutamate transmission. By establishing a link between ELA and circuit mechanisms underlying behavioral flexibility, our findings will begin to identify novel molecular mechanisms that can represent strategies for treating behavioral inflexibility in individuals who experienced early life traumatic incidents.

Neurexins (Nrxns) have been extensively studied for their role in synapse organization and have been linked to many neuropsychiatric disorders, including autism spectrum disorder (ASD), and epilepsy. However, no studies have provided direct evidence that Nrxns may be the key regulator in the shared pathogenesis of these conditions largely due to complexities among Nrxns and their non-canonical functions in different synapses. Recent studies identified NRXN2 mutations in ASD and epilepsy, but little is known about Nrxn2’s role in a circuit-specific manner. Here, we report that conditional deletion of Nrxn2 from the hippocampus and cortex (Nrxn2 cKO) results in behavioral abnormalities, including reduced social preference and increased nestlet shredding behavior. Electrophysiological recordings identified an overall increase in hippocampal CA3◊CA1 network activity in Nrxn2 cKO mice. Using intracranial electroencephalogram recordings, we observed unprovoked spontaneous reoccurring electrographic and behavioral seizures in Nrxn2 cKO mice. This study provides the first evidence that conditional deletion of Nrxn2 induces increased network activity that manifests into spontaneous recurrent seizures and behavioral impairments.