Sex-Dependent Novelty Response in Neurexin-1α Mutant Mice

Laarakker, Marijke C.; Reinders, Niels R.; Bruining, Hilgo; Ophoff, Roel A.; Kas, Martien

doi:10.1371/journal.pone.0031503

Cited by 41 publications

(48 citation statements)

References 38 publications

(35 reference statements)

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“…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).…”

Section: Unraveling the Mystery Of Higher Asd Rates In Boys Compared mentioning

confidence: 99%

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

McCarthy

Wright

2017

Biological Psychiatry

131

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The male bias in autism spectrum disorder incidence is among the most extreme of all neuropsychiatric disorders, yet the origins of the sex difference remain obscure. Developmentally males are exposed to high levels of testosterone and its byproduct, estradiol. Together these steroids modify the course of brain development by altering neurogenesis, cell death, migration, differentiation, dendritic and axonal growth, synaptogenesis and synaptic pruning, all of which can be deleteriously impacted during the course of developmental neuropsychiatric disorders. Elucidating the cellular mechanisms by which steroids modulate brain development provides valuable insights into how these processes may go awry. An emerging theme is the role of inflammatory signaling molecules and the innate immune system in directing brain masculinization, the evidence for which we review here. Likewise evidence is emerging that the neuroimmune system is over-activated in individuals with autism spectrum disorder. These combined observations lead us to propose that the natural process of brain masculinization puts males at risk by moving them closer to a vulnerability threshold that could more easily be breached by inflammation during critical periods of brain development. Two brain regions are highlighted, the preoptic area and the cerebellum. Both are developmentally regulated by the inflammatory prostaglandin, PGE2, but in very different ways. Microglia, innate immune cells of the brain, and astrocytes are also critical contributors to masculinization and illustrate the importance of non-neuronal cells to the health of the developing brain.

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Section: Unraveling the Mystery Of Higher Asd Rates In Boys Compared mentioning

confidence: 99%

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

McCarthy

Wright

2017

Biological Psychiatry

131

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“…Approximately 0.5% of ASD cases harbor mutations in Nrxn 1a (NRXN1), underlining the importance of this gene in the etiology of NDDs (Reichelt et al, 2012). Analyses with loss-of-function mutations of the Nrxn genes have confirmed the role of a-Nrxns in shaping synapse function (Missler et al, 2003;Sons et al, 2006) and complex behaviors (Etherton et al, 2009;Laarakker et al, 2012), including social behaviors (Grayton et al, 2013). Deletion of all three a-Nrxn genes results in death of newly born mouse pups because of reduced synaptic transmission (Missler et al, 2003).…”

Section: Neuronal Contactmentioning

confidence: 99%

Synapse Assembly and Neurodevelopmental Disorders

Washbourne

2014

Neuropsychopharmacol

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“…Further, sex-dependent differences in response to novelty and habituation processes have also been observed (Laarakker, Reinders, Bruining, Ophoff, & Kas, 2012).…”

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confidence: 97%

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

Esclassan¹,

François²,

Phillips³

et al. 2015

Behavioral Neuroscience

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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.

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Sex-Dependent Novelty Response in Neurexin-1α Mutant Mice

Cited by 41 publications

References 38 publications

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

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

Synapse Assembly and Neurodevelopmental Disorders

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

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