Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder

Abstract

The chromosome 15q13.3 microdeletion is a pathogenic copy number variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/ϩ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/ϩ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/ϩ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia.

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

“…Reduced AEP response in Df(h15q13)/+ mice has previously been shown in a similar paradigm with EEG measurements (Fejgin et al 2014, Kogan et al 2015, and we found that this difference is also present at the level of single cell responses. When averaging the evoked responses of all recorded cells in A1 in terms of increase in firing rate from baseline average rate, a reduced response amplitude was observed in the Df(h15q13)/+ mice.…”

“…Recently, encephalography (EEG) recordings in a mouse model of the 15q13.3 microdeletion syndrome, Df(h15q13)/+ mice, have been published (Fejgin et al 2014), and the mice display reduced excitability and reduced capacity to generate cortical evoked gamma oscillations. This finding has been reproduced in an independent 15q13.3 deletion mouse line (Kogan et al 2015). A possible cause for reduced cortical gamma oscillations is dysfunctional local cortical networks.…”

“…2014, Kogan et al . 2015). Even though standard EEG recordings (frequency < 100 Hz) primarily reflect mass post‐synaptic potentials rather than action potentials (Telenczuk et al .…”

“…This finding has been reproduced in an independent 15q13.3 deletion mouse line (Kogan et al . 2015). A possible cause for reduced cortical gamma oscillations is dysfunctional local cortical networks.…”

Autism spectrum disorder: neuropathology and animal models

“…A recently developed heterozygous deletion D/+ mouse model with a homologous microdeletion has enlarged brains and lateral ventricles in adulthood [204]; enlarged head size has been observed in subjects with the microdeletion [272]. Although neuron number and dendritic morphology were not quantified in the D/+ mice, no gross differences were observed [204]. …”