Repetitive grooming and sensorimotor abnormalities in an ephrin-A knockout model for Autism Spectrum Disorders

Abstract

EphA receptors and ephrin-A ligands play important roles in neural development and synaptic plasticity in brain regions where expression persists into adulthood. Recently, EPHA3 and EPHA7 gene mutations were linked with Autism Spectrum Disorders (ASDs) and developmental neurological delays, respectively. Furthermore, deletions of ephrin-A2 or ephrin-A3, which exhibit high binding affinity for EphA3 and EphA7 receptors, are associated with subtle deficits in learning and memory behavior and abnormalities in dendritic spine morphology in the cortex and hippocampus in mice. To better characterize a potential role for these ligands in ASDs, we performed a comprehensive behavioral characterization of anxiety-like, sensorimotor, learning, and social behaviors in ephrin-A2/-A3 double knockout (DKO) mice. The predominant phenotype in DKO mice was repetitive and self-injurious grooming behaviors such as have been associated with corticostriatal circuit abnormalities in other rodent models of neuropsychiatric disorders. Consistent with ASDs specifically, DKO mice exhibited decreased preference for social interaction in the social approach assay, decreased locomotor activity in the open field, increased prepulse inhibition of acoustic startle, and a shift towards self-directed activity (e.g., grooming) in novel environments, such as marble burying. Although there were no gross deficits in cognitive assays, subtle differences in performance on fear conditioning and in the Morris water maze resembled traits observed in other rodent models of ASD. We therefore conclude that ephrin-A2/-A3 DKO mice have utility as a novel ASD model with an emphasis on sensory abnormalities and restricted, repetitive behavioral symptoms.

Neurobiology of rodent self-grooming and its value for translational neuroscience

“…Ephrin A ligands and ephrin A receptors are strongly implicated in neurodevelopment 115 . Ephrin A ligands are membrane-anchored cellular proteins that bind to ephrin A receptors, members of the receptor tyrosine kinase superfamily.…”

“…Ephrin A ligands are membrane-anchored cellular proteins that bind to ephrin A receptors, members of the receptor tyrosine kinase superfamily. During development, ephrin A-mediated signalling modulates neuronal differentiation and synaptic plasticity 115 . Because ASD is a neurodevelopmental disorder, ephrin A ligands and their receptors may be relevant to ASD and modelling its pathogenesis in animals 115 .…”

Autism Spectrum Disorders: Translating human deficits into mouse behavior

“…Using videotaped sessions, investigators blind to the genotype or treatment score repetitive self-grooming as the total time spent grooming during a specific testing period Spencer et al, 2011a). In some cases, the mouse's face is mildly wetted to stimulate grooming (Wurzman et al, 2015). High levels of repetitive self-grooming have been reported for two inbred mouse models of ASD, C58/J and BTBR T + tf/J Silverman et al, 2012).…”

Stress increases GABAergic neurotransmission in CRF neurons of the central amygdala and bed nucleus stria terminalis

“…For 8 habituation of the acoustic startle response, animals were tested in the SRLab startle 9 system (San Diego Instruments) and presented with a series of five 120dB white noise 10 pulses, followed by prepulse inhibition trials as previously described (Washington et al, 11 2012;Wurzman et al, 2014), followed by another five 120dB white noise pulses. 12…”