Abstract
Autism spectrum disorders (ASD) are pervasive neurodevelopmental conditions detected during childhood when delayed language onset and social deficits are observed. Children diagnosed with ASD frequently display sensorimotor deficits associated with the cerebellum, suggesting a dysfunction of synaptic circuits. Astroglia are part of the tripartite synapses and postmortem studies reported an increased expression of the glial fibrillary acidic protein (GFAP) in the cerebellum of ASD patients. Astroglia respond to neuronal activity with calcium transients that propagate to neighboring cells, resulting in a functional response known as a calcium wave. This form of intercellular signaling is implicated in proliferation, migration, and differentiation of neural precursors. Prenatal exposure to valproate (VPA) is a preclinical model of ASD in which premature migration and excess of apoptosis occur in the internal granular layer (IGL) of the cerebellum during the early postnatal period. In this study we tested calcium wave propagation in the IGL of mice prenatally exposed to VPA. Sensorimotor deficits were observed and IGL depolarization evoked a calcium wave with astrocyte recruitment. The calcium wave propagation, initial cell recruitment, and mean amplitude of the calcium transients increased significantly in VPA-exposed mice compared to the control group. Astrocyte recruitment was significantly increased in the VPA model, but the mean amplitude of the calcium transients was unchanged. Western blot and histological studies revealed an increased expression of GFAP, higher astroglial density and augmented morphological complexity. We conclude that the functional signature of the IGL is remarkably augmented in the preclinical model of autism.
Highlights
Autism Spectrum Disorder (ASD) refers to a group of neurodevelopmental disorders characterized by social impairment, communication deficits, stereotypies, and repetitive behaviors
Astroglia are part of the tripartite synapses and respond to neuronal activity with calcium transients that propagate to neighboring cells, a signaling mode known as a calcium wave (Schipke and Kettenmann, 2004; Perea and Araque, 2005)
The VPA-treated mice with autistic-like sensorimotor deficits were selected and acute slices containing the Crus I/Crus II regions of the cerebellum were depolarized at the internal granular layer (IGL) to evoke a calcium wave (Figure 2A)
Summary
Autism Spectrum Disorder (ASD) refers to a group of neurodevelopmental disorders characterized by social impairment, communication deficits, stereotypies, and repetitive behaviors. Bioinformatic studies have shown that ASD gene-associated co-expression networks are highly expressed in the cerebellar granule layer and that genes involved in calcium signaling are proposed to be dysregulated in the developing brain of autistic children (Menashe et al, 2013; Zeidán-Chuliá et al, 2013). It is unknown whether neuron-glia communication associated with calcium signaling is disturbed in the early neurodevelopment of the autistic brain.
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