Advances in neurexin studies and the emerging role of neurexin-2 in autism spectrum disorder

Abstract

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.

Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization

“…Thus, JNK signaling could be a key factor that defines the sex-dependent behavioral phenotypes of Nrxn2α KO mice. In addition, given the high implication of Nrxn2 and JNKs in neurodevelopmental disorders such as autism spectrum disorders ( Coffey, 2014 ; Khoja et al, 2023 ), it will be very important to gain more insights into the relationship between JNK signaling and Nrxns.…”

Conditional deletion of Neurexin-2 alters neuronal network activity in hippocampal circuitries and leads to spontaneous seizures

“…26-84% of patients diagnosed with Phelan-McDermid syndrome exhibit ASDlike behavioral traits, demonstrating ASD as the common comorbidity [78,79]. Considering that 14% of all NRXN2 mutations reported have resulted in both ASD and ASD-associated disorders (Supplemental Table 1), the Nrxn2 cKO mouse model is a valuable genetic tool to study biological pathways underlying the comorbidity of ASD with epilepsy and other neurodevelopmental disorders [80]. Overall, our findings will be a stepping stone toward establishing a role for Nrxn2 in the pathogenesis of disorders characterized by hyperexcitability and altered social behaviors including ASD and co-morbid neurological and developmental disorders.…”

Neurexin dysfunction in neurodevelopmental and neuropsychiatric disorders: a PRIMSA-based systematic review through iPSC and animal models

“…Neurexins, primarily transcribed from three genes (in animals: Nrxn1, Nrxn2, Nrxn3; in humans: NRXN1, NRXN2, NRXN3) ( Khoja et al, 2023 ), are pivotal presynaptic adhesion proteins within the nervous system. These proteins play critical roles in synapse formation and function, manifesting in two primary forms: the longer α-neurexins and the shorter β-neurexins ( Reissner et al, 2013 ; Zhang et al, 2022 ; Trotter et al, 2023 ).…”

“…In contrast, a single disorder could also result from different deletions of neurexin genes. For example, dysfunctions across all three neurexin genes (i.e., NRXN 1–3) have been identified as contributors to a disrupted balance between excitatory and inhibitory neurotransmission in human ASD ( Khoja et al, 2023 ). These findings further highlight the need to figure out the complex association between neurexins and these disorders.…”