Neurexin-2: An inhibitory neurexin that restricts excitatory synapse formation in the hippocampus

Abstract

Neurexins are widely thought to promote synapse formation and to organize synapse properties. Here we found that in contrast to neurexin-1 and neurexin-3, neurexin-2 unexpectedly restricts synapse formation. In the hippocampus, constitutive or neuron-specific deletions of neurexin-2 nearly doubled the strength of excitatory CA3➔CA1 region synaptic connections and markedly increased their release probability. No effect on inhibitory synapses was detected. Stochastic optical reconstruction microscopy (STORM) superresolution microscopy revealed that the neuron-specific neurexin-2 deletion elevated the density of excitatory CA1 region synapses nearly twofold. Moreover, hippocampal neurexin-2 deletions also increased synaptic connectivity in the CA1 region when induced in mature mice and impaired the cognitive flexibility of spatial memory. Thus, neurexin-2 controls the dynamics of hippocampal synaptic circuits by repressing synapse assembly throughout life, a restrictive function that markedly differs from that of neurexin-1 and neurexin-3 and of other synaptic adhesion molecules, suggesting that neurexins evolutionarily diverged into opposing pro- and antisynaptogenic organizers.

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

“…Neuron-specific deletion of Nrxn2 was employed to account for glial contributions to synaptic phenotypes. Lin et al discovered (1) the constitutive deletion of Nrxn2 gene increased hippocampal CA3 to CA1 synaptic connections, (2) neuron-specific deletion of Nrxn2 gene increased CA3 to CA1 synaptic connectivity, release probability, and excitatory synapse density in the CA1 region, (3) conditional deletion of Nrxn2 gene enhanced CA3 to CA1 synaptic connections (Lin et al, 2023). Taken together, this comprehensive study suggests that Nrxn2 regulates synaptic connectivity by restricting excitatory synaptic connections in hippocampal circuits.…”

“…While these studies are informative, they do not address the synapse specificity required to effectively study Nrxn2. Moreover, the Nrxn2αβ mouse model by Born et al (Born et al, 2015) was never able to show complete deletion of Nrxn2 gene, and the mouse generated was later abandoned because there was no clear evidence that Nrxn2 gene was deleted (Lin et al, 2023). The first study to comprehensively examine Nrxn2 employed constitutive, conditional and neuron-specific deletion strategies.…”

“…Findings from Lin et al (2023) showed that Nrxn2 regulates synaptic connectivity by inhibiting excitatory synaptic connections in hippocampal circuits. Whether excitatory or inhibitory neuron specific Nrxn2 regulates this restrictive function on excitatory synapses remains unclear.…”

“…In the domain of repetitive behaviors, male, but not female, Nrxn2 KO mice exhibited increased nestlet shredding behavior without any impairments in other measures of repetitive behaviors including self-grooming, jumping and marbles buried; however, these findings were not accompanied by ASD-related associated symptoms including anxiety-like behavior and working memory deficits (Haile et al, 2022). Another study analyzed hippocampal-specific deletion of Nrxn2 gene on day 24 postpartum (dpp; Lin et al, 2023). This group did not observe alterations in open field test, fear conditioning or passive avoidance tests, but a small impairment in the rotarod test was observed in Nrxn2 cKO mice (Lin et al, 2023).…”

“…Another study analyzed hippocampal-specific deletion of Nrxn2 gene on day 24 postpartum (dpp; Lin et al, 2023). This group did not observe alterations in open field test, fear conditioning or passive avoidance tests, but a small impairment in the rotarod test was observed in Nrxn2 cKO mice (Lin et al, 2023). Interestingly, the Nrxn2 cKO mice were able to acquire the location of hidden platform in the water T-maze test as quickly as the WT littermates but exhibited reversal learning deficits suggesting a role for hippocampal Nrxn2 in cognitive flexibility (Lin et al, 2023).…”