Phenotypic characterization of nonsocial behavioral impairment in neurexin 1α knockout rats.

Abstract

Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients. NRXN1-α knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy. At present, a thorough assessment of cognitive function has yet to be completed. Rats, containing a biallelic deletion of the NRNX1-α gene on a Sprague Dawley background were compared to littermate wild types across a range of tasks designed to test functional domains disrupted in ASD and other neurodevelopmental disorders, including sensory perception (prepulse inhibition), attention (latent inhibition), associative learning (instrumental and Pavlovian conditioning), and memory (rewarded alternation T maze and spatial discrimination). NRXN1α KO rats were found to present with large and persistent nonsocial deficits, including hyperactivity, deficits in simple instrumental learning, latent inhibition, and spatial-dependent learning. No deficit in sensorimotor gating was observed, despite the presence of an exaggerated startle response. Although KO animals were also able to learn a simple Pavlovian conditioning discrimination, they did display impaired latent inhibition. The presence of pronounced impairments in several domains in NRXN1α KO rats clearly suggests that nonsocial cognitive deficits can also be measured in an animal model of ASD. Further exploration of those deficits, both clinically and preclinically, as planned in the Innovative Medicines Initiative's European Autism Interventions: A Multicenter Study for Developing New Medications program, may help to better understand the brain circuitry involved in ASD and therefore open new avenues to advance novel therapies.

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…Homo- and heterozygous Nrxn1α KO mice exhibited an array of behavioral impairments, including impaired nest building, decreased pre-pulse inhibition, and social interaction deficits (Etherton et al, 2009; Grayton et al, 2013; Dachtler et al, 2015; Esclassan et al, 2015), that may be related to neuropsychiatric disorders and support the notion that NRXN1 deletions in human patients significantly contribute to the development of symptoms.…”

Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder

“…The last two questions are amenable to experimental approaches using animal models. Determining how sex contributes to liability for ASD can be achieved by looking for sex differences in the impact of deletions or mutations of ASD risk genes as has been done in many mouse (30) and limited rat models (31, 32). For instance, Nrxn1 is a strong candidate ASD risk gene.…”

“…There are social impairments in the homozygous Nrxn1 KO mouse (33) and a male-specific effect on novelty (34). Preliminary analyses of Nrxn1 KO rats finds hyperactivity and cognitive impairments, some of which are specific to males (32). But there are relatively few other examples of an ASD candidate risk gene explored in the context of sex differences.…”

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

“…Other genetic ASD-relevant rat KO models are the neuroligin-3 ( Nlgn3 ) null and the neurexin-1α ( Nrxn1-α ) KO rats model. Nlgn3 KO rats display reduced juvenile social play (Hamilton et al 2014), while Nrxn1-α KO rats exhibit hyperactivity, exaggerated startle responses, and impairments in latent inhibition and spatial-dependent learning (Esclassan et al 2015). Genetic rat models of autism offer a new set of tools for evaluating pharmacological interventions.…”