Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit

Division of Clinical Neuroscience, Max Planck Institute for Experimental Medicine, Göttingen, Germany.
Genes Brain and Behavior (Impact Factor: 3.51). 03/2009; 8:416-425. DOI: 10.1111/j.1601-183X.2009.00487.x

ABSTRACT Autism spectrum disorder (ASD) is a frequent neurodevelopmental disorder characterized by variable clinical severity. Core symptoms are qualitatively impaired communication and social behavior, highly restricted interests and repetitive behaviors. Although recent work on genetic mutations in ASD has shed light on the pathophysiology of the disease, classifying it essentially as a synaptopathy, no treatments are available to date. To develop and test novel ASD treatment approaches, validated and informative animal models are required. Of particular interest, in this context are loss-of-function mutations in the postsynaptic cell adhesion protein neuroligin-4 and point mutations in its homologue neuroligin-3 (NL-3) that were found to cause certain forms of monogenic heritable ASD in humans. Here, we show that NL-3-deficient mice display a behavioral phenotype reminiscent of the lead symptoms of ASD: reduced ultrasound vocalization and a lack of social novelty preference. The latter may be related to an olfactory deficiency observed in the NL-3 mutants. Interestingly, such olfactory phenotype is also present in a subgroup of human ASD patients. Tests for learning and memory showed no gross abnormalities in NL-3 mutants. Also, no alterations were found in time spent in social interaction, prepulse inhibition, seizure propensity and sucrose preference. As often seen in adult ASD patients, total brain volume of NL-3 mutant mice was slightly reduced as assessed by magnetic resonance imaging (MRI). Our findings show that the NL-3 knockout mouse represents a useful animal model for understanding pathophysiological events in monogenic heritable ASD and for developing novel treatment strategies in this devastating human disorder.

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    ABSTRACT: Epilepsy is a common comorbidity in patients with Autism spectrum disorder (ASD) and several gene mutations are associated with both of these disorders. In order to determine whether a point mutation in the gene for the synaptic protein, neuroligin-3 (Nlgn3, R451C), identified in patients with ASD alters seizure susceptibility, we administered the proconvulsant pentylenetetrazole (PTZ) to adult male Neuroligin-3(R451C) (NL3(R451C)) and wild type (WT) mice. It has previously been reported that NL3(R451C) mice show altered inhibitory GABAergic activity in brain regions relevant to epilepsy, including the hippocampus and somatosensory cortex. PTZ administration induces absence-seizures at low dose, and generalised convulsive seizures at higher dose. Susceptibility to absence seizures was examined by analysing the frequency and duration of spike-and-wave discharge (SWD) events and accompanying motor seizure activity induced by subcutaneous administration of low dosage (20 or 30 mg/kg) PTZ. Susceptibility to generalised convulsive seizures was tested by measuring the response to high dosage (60 mg/kg) PTZ using a modified Racine scale. There was no change in the number of SWD events exhibited by NL3(R451C) compared to WT mice following administration of both 20 mg/kg PTZ (1.17 ± 0.31 compared to 16.0 ± 11.16 events/30 min, NL3(R451C) vs WT respectively) and 30 mg/kg PTZ (7.5 ± 6.54 compared with 27.8 ± 19.9 events/30 min, NL3(R451C) versus WT respectively). NL3(R451C) mice were seizure resistant to generalised convulsive seizures induced by high dose PTZ compared to WT littermates (median latency to first > 3 s duration clonic seizure; 14.5 min versus 7.25 min, 95% CI: 1.625-2.375, p = 0.0009, NL3(R451C) vs WT respectively). These results indicate that the R451C mutation in the Nlgn3 gene, associated with ASD in humans, confers resistance to induced seizures, suggesting dysfunction of PTZ-sensitive GABAergic signalling in this mouse model of ASD. Copyright © 2015. Published by Elsevier Ireland Ltd.
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