title: Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism.
abstract: Autism is the short name of a complex and heterogeneous group of disorders (autism spectrum disorders, ASD) with several lead symptoms required for classification, including compromised social interaction, reduced verbal communication and stereotyped repetitive behaviors/restricted interests. The etiology of ASD is still unknown in most cases but monogenic heritable forms exist that have provided insights into ASD pathogenesis and have led to the notion of autism as a 'synapse disorder'. Among the most frequent monogenic causes of autism are loss-of-function mutations of the NLGN4X gene which encodes the synaptic cell adhesion protein neuroligin-4X (NLGN4X). We previously described autism-like behaviors in male Nlgn4 null mutant mice, including reduced social interaction and ultrasonic communication. Here, we extend the phenotypical characterization of Nlgn4 null mutant mice to both genders and add a series of additional autism-relevant behavioral readouts. We now report similar social interaction and ultrasonic communication deficits in females as in males. Furthermore, aggression, nest-building parameters, as well as self-grooming and circling as indicators of repetitive behaviors/stereotypies were explored in both genders. The construction of a gender-specific autism severity composite score for Nlgn4 mutant mice markedly diminishes population/sample heterogeneity typically obtained for single tests, resulting in p values of <0.00001 and a genotype predictability of 100% for male and of >83% for female mice. Taken together, these data underscore the similarity of phenotypical consequences of Nlgn4/NLGN4X loss-of-function in mouse and man, and emphasize the high relevance of Nlgn4 null mutant mice as an ASD model with both construct and face validity.
authors.affiliation: Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Kordi
authors.forename: Daniela
authors.initials: D
authors.lastname: Winkler
authors.forename: Kurt
authors.initials: K
authors.lastname: Hammerschmidt
authors.forename: Anne
authors.initials: A
authors.lastname: Kästner
authors.forename: Dilja
authors.initials: D
authors.lastname: Krueger
authors.forename: Anja
authors.initials: A
authors.lastname: Ronnenberg
authors.forename: Caroline
authors.initials: C
authors.lastname: Ritter
authors.forename: Jasmin
authors.initials: J
authors.lastname: Jatho
authors.forename: Konstantin
authors.initials: K
authors.lastname: Radyushkin
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeron
authors.forename: Julia
authors.initials: J
authors.lastname: Fischer
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006120:Grooming / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012720:Severity of Illness Index; D012727:Sex Characteristics; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000502:physiology; D014828:Vocalization, Animal / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; C527118:Nlgn4 protein, mouse