Altered cerebellar response to somatosensory stimuli in the Cntnap2 mouse model of autism

Abstract

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied cerebellar integration of sensory information in a mouse model of autism, knockout for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in this mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice and found striking differences between WT and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These alterations were accompanied by altered intrinsic properties and morphological features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of ASD core sensory deficits.

Cntnap2loss drives striatal neuron hyperexcitability and behavioral inflexibility

“…The loss of Caspr2 has a variable impact on intrinsic excitability across brain regions and cell types. The increased intrinsic excitability that we identified in SPNs has also been observed in Purkinje cells of the cerebellum (Fernandez et al, 2021) and pyramidal cells of the cortex (Antoine et al, 2019;Cifuentes-Diaz et al, 2023). However, we note hypoactivity (Brumback et al, 2018) or unchanged excitability (Lazaro et al, 2019) of pyramidal cells in some cortical regions in Cntnap2 -/mice.…”

The NO Answer for Autism Spectrum Disorder

“…Protein expression of Homer and PSD-95 was unchanged in both the cortex (Figure 4A,G,H) and the striatum (Figure S1C,F, Supporting Information). In M2 mouse cortical neurons the spine density (the dendritic spine number) levels increased following 7-NI treatment, [59] compared with the M2 group (Figure 4M). No changes were found in the expression of all the above-mentioned proteins after 7-NI treatment to the WT1 group (Figures 4A-I).…”

Cerebellar Plasticity Changes in an Experimental Model of Autism Induced by Maternal Separation

“…Although the role of many genes in autism has been shown [3], recent studies show that important environmental factors such as nutrition, the use of certain drugs such Journal of Neurodevelopmental Cognition 3 (2023) 9-15 ISSN: 2645-565X ! ""#$%%&&&'()*+,'-./'0*' 12 Mansouri, Mashayekhi, and Ardalan as sodium valproate and most importantly psychological factors in the first years of life, such as poor communication of parents or caregivers with the child and generally not having an environment rich in sufficient sensory and psychological stimuli can play a role in the development and exacerbation of autism-related behaviors [4]. To understand autism, various animal models have been developed based on genetic manipulation and environmental interventions [5,6].…”

“…Due to the causal and phenotypic complexity of the ASD, the study of the other areas of the brain to clearly find changes under existing conditions is of importance. The cerebellum is one of the brain regions highly regarded in autism today [11]. Although it is traditionally involved in motor function, there is ample evidence that is also involved in cognitive functions [12].…”

“…The cerebellum is one of the brain regions highly regarded in autism today [11]. Although it is traditionally involved in motor function, there is ample evidence that is also involved in cognitive functions [12]. Some studies show that the cerebellum is structurally and functionally abnormal in patients with autism [12].…”