Assessing the developmental trajectory of mouse models of neurodevelopmental disorders: Social and communication deficits in mice with Neurexin 1α deletion

Abstract

Neurexin 1α mutations are strongly associated with neurodevelopmental disorders such as autism spectrum disorders and schizophrenia in humans. Studies using the Neurexin 1α knock‐out mouse have showed behavioral abnormalities of relevance to these disorders and baseline deficits in excitatory synaptic function have been described. However, little is known about the effect of Neurexin 1α deletion on behavior during development. This study examined the effects of Neurexin 1α deletion on behavior across a range of developmental time points to determine whether potential abnormalities follow a developmental trajectory. Pups lacking Neurexin 1α emitted a reduced number of ultrasonic vocalizations early in development combined with a restricted repertoire of calls indicative of a loss in complexity in vocal production and showed delays in reaching certain developmental milestones. Behavioral testing showed that juvenile and adult male Neurexin 1α knock‐out mice exhibited social deficits and increased levels of aggression, confirming previous findings. No increases in repetitive behaviors or deficits in motor learning or olfaction were seen. In conclusion, this research showed that Neurexin 1α deletion does result in social and communication deficits that follow a developmental trajectory. These are the first experimental data that associate a deletion of Neurexin 1α with alterations in behaviors relevant to autism spectrum disorder across development and highlight the importance of assessing the developmental trajectory in mouse models of neurodevelopmental disorders.

Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder

“…Mice lacking Nrxn1 exhibit deficits in core symptoms related to ASD. Specifically, Nrxn1α mutants display deficits in the social domain including increased social preference, decreased social investigation, decreased social interaction, and increased aggression [ 35 , 46 , 47 , 48 ]. Furthermore, they show stereotypic and repetitive behaviors such as increased grooming, impaired nest-building, altered novelty responsiveness, and habituation [ 31 , 35 , 38 ].…”

“…Furthermore, they show stereotypic and repetitive behaviors such as increased grooming, impaired nest-building, altered novelty responsiveness, and habituation [ 31 , 35 , 38 ]. In addition, several behaviors were reported that relate to ASD comorbidities including deficits in learning and cognition, locomotor activity, motor performance, award processing, and anxiety-like behaviors [ 31 , 35 , 36 , 38 , 46 , 47 , 48 , 49 ]. Although the social, stereotyped, and repetitive behaviors are commonly studied, sensory behaviors have received less attention in this model.…”

“…Since social behaviors heavily rely on olfactory cues, the observed differences in social behavior might therefore not be due to deficits in olfaction [ 47 ]. However, Nrxn1 knockout mice show increased responses to auditory stimuli, seen by increases in startle responses to 80–100 dB auditory stimuli and increased startle response to 120 dB startle, indicating altered auditory sensitivity [ 31 , 36 ] In addition, while acoustic pre-pulse inhibition does not seem to be affected in heterozygous knockout mice or rat model [ 46 ], homozygous knockout mice display a decrease in pre-pulse inhibition [ 35 , 46 , 47 ]. Lastly, Nrxn1 knockout rats display decreased eye-blink conditioning, indicating altered cerebral sensory learning [ 48 ].…”

Interaction Between the Intestinal Microbial Community and Transcriptome Profile in Common Carp (Cyprinus carpio L.)

“…These genes may be associated with the higher muscle polyunsaturated fatty acid content in this new carp strain ( Shengyan et al, 2018 ). The last class is associated with nerve regulation; e.g., neurexin-1a is strongly associated with neurodevelopmental disorders, so knockout mice exhibited social deficits and increased levels of aggression ( Armstrong et al, 2020 ); Krueppel-like factor 13 inhibits neurite/axon growth in hippocampal neurons partially by inhibiting the cAMP signaling pathway ( Ávila-Mendoza et al, 2020 ). These nerve regulation-related genes may be a reflection of the microbiota-gut-brain axis ( Cryan et al, 2019 ).…”

Atypical Teratoid Rhabdoid Tumours Are Susceptible to Panobinostat-Mediated Differentiation Therapy

“…Detailed inspection of these functional groups further revealed enrichment of genes that are essential in nervous system development (Figure 4a,b). Several key promoters and regulators in central nervous system development (Nitric Oxide Synthase 1 (NOS1) [33][34][35][36]), neuron differentiation (T-box Transcription Factor 3 (TBX3) [37], Desmoplakin 3 (DPF3) [38,39], Bone Morphogenetic Protein 4 (BMP4) [37,40]) and neuronal development (Neurexin 2 (NRXN2) [41,42], Ataxin 1 (ATXN1) [43,44]) were upregulated, supporting neuronal differentiation [45] (Figure 4a,b). Additionally, there was also a prevalence of functional groups associated with cell division regulation including the mitotic cell cycle, nuclear division, regulation of metaphase/anaphase transition of the cell cycle, regulation of chromosome separation and spindle organization (Figure 3c,d).…”