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

Abstract

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.

Rare heterozygous genetic variants of NRXN and NLGN gene families involved in synaptic function and their association with neurodevelopmental disorders

“…Furthermore, subsequent studies have also supported the association of the NRXN2 with ASD (Cukier et al, 2014;Haile et al, 2023;Hu et al, 2023;Li et al, 2017;Lim et al, 2017;Wu et al, 2018). A total of 118 different NRXN2 variants have been reported, including benign and likely benign variants (Haile et al, 2023). Supporting these previous findings, we detected a heterozygous NRXN2 gene variant (c.808dup) in two unrelated cases diagnosed with ID/DD.…”

“…The association between ASD and NRXN2 gene was first demonstrated by Gauthier et al in 2011. In their study of individuals with ASD (n = 142), schizophrenia (n = 143), or non-syndromic ID (n = 94), they identified a NRXN2 gene: NM_138732.2: c.2733delT variant in a patient with ASD (Gauthier et al, 2011). Furthermore, subsequent studies have also supported the association of the NRXN2 with ASD (Cukier et al, 2014;Haile et al, 2023;Hu et al, 2023;Li et al, 2017;Lim et al, 2017;Wu et al, 2018). A total of 118 different NRXN2 variants have been reported, including benign and likely benign variants (Haile et al, 2023).…”

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

“…There are several functional differences between Nrxn2 and the other neurexins. As an extreme example, recent studies have shown a unique role of Nrxn2 in excitatory synapse function in which Nrxn2 acts as anti-synaptogenic organizer, which is at odds with the roles of Nrxn1/3 ( Haile et al, 2023 ; Lin et al, 2023 ). One reason for functional differences between Nrxn2α and the other α-neurexins may be their high degree of molecular divergence.…”

“…Thus, estrogen-related signal transduction may control the functional linkage between Nrxns and JNKs and consequently lead to sex differences in modulation of neurotransmission. Interestingly, JNK1 KO mice exhibit increased explorative behaviors ( Reinecke et al, 2013 ), reminiscent of Nrxn2 KO male but not female mice ( Haile et al, 2023 ). On the other hand, deletion of Nrxn2 α leads to reduced sociability in female but not male mice.…”