Neurexin Dysfunction in Adult Neurons Results in Autistic-like Behavior in Mice

Abstract

Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes characterized by repetitive behavior and social and communication deficits. Autism is generally viewed as a neurodevelopmental disorder where insults during embryonic or early postnatal periods result in aberrant wiring and function of neuronal circuits. Neurexins are synaptic proteins associated with autism. Here, we generated transgenic βNrx1ΔC mice in which neurexin function is selectively impaired during late postnatal stages. Whole-cell recordings in cortical neurons show an impairment of glutamatergic synaptic transmission in the βNrx1ΔC mice. Importantly, mutant mice exhibit autism-related symptoms, such as increased self-grooming, deficits in social interactions, and altered interaction for nonsocial olfactory cues. The autistic-like phenotype of βNrx1ΔC mice can be reversed after removing the mutant protein in aged animals. The defects resulting from disruption of neurexin function after the completion of embryonic and early postnatal development suggest that functional impairment of mature circuits can trigger autism-related phenotypes.

Autism Spectrum Disorders: Translating human deficits into mouse behavior

“…However, the deficits observed in social interaction and communications are not always accompanied by alterations on olfaction, as seen in Itgb3 -/-mice (Carter et al, 2011). Interestingly, in a recent report the βNrx1ΔC mice (with impaired neurexin function) did not show a clear preference for the social cues compared with the nonsocial cues, as observed with control animals (Rabaneda et al, 2014). Shank3 -/-mutant mice performed similar to control animals in the olfactory discrimination task Wang et al, 2011;Yang et al, 2012).…”

“…Resident-intruder test Jiang-Xie et al, 2014a;Page, 2014, 2015. Communication Ultrasonic vocalization Pup isolation from mother Wohr et al2011;Schmeisser et al 2012;Yang et al 2012;Ey et al 2013;Wohr 2014,GreeneColozzi et al2014Scattoni et al, 2009;Young et al, 2010;Fujita et al, 2008;Shu et al, 2005;Ju et al, 2014. Female-male/malemale interaction Bozdagi et al 2010;Wohr et al 2011;Schmeisser et al 2012;Won et al 2012; Discrimination of social odors Olfactory discrimination tasks Tsai et al, 2012;Rabaneda et al, 2014. Restricted and repetitive patterns of behavior…”

Glutamate Synapses in Human Cognitive Disorders

“…NRXN3 mutation has also recently been implicated in ASD (Vaags et al 2012). Both Nrxn1α knockout mice and mice overexpressing dominant-negative NRXN1β exhibit ASD-related behavioral abnormalities (Rabaneda et al 2014).…”

The utility of rodent models of autism spectrum disorders

“…Behavioral measures are indispensable for gauging of effect and drug treatments and therapeutics. Fourth, the advent of models that allow temporally-specific genetic deletion and rescue of ASD-related genetic changes, would allow us to define the critical developmental windows where interventions would be effective [11–14]. Many of these genetic changes may not only alter brain development but also affect the function of fully-developed brain circuits [15].…”