A Functional Signature in the Developing Cerebellum: Evidence From a Preclinical Model of Autism

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.

Photobiomodulation Attenuated Cognitive Dysfunction and Neuroinflammation in a Prenatal Valproic Acid-Induced Autism Spectrum Disorder Mouse Model

“…The righting reflex test measured the pup's ability to regain its footing from the supine position [57]. At P10-13, the pups were placed on their backs on a flat surface and held in that position for 5 s. The time it took for each pup to return to the prone position after being released was recorded.…”

Morphological characteristics of astrocytes of the fastigial nucleus

“…The GFAP-eGFP transgenic mouse line facilitated the identification of astrocytes in the FN and the inspection of their distribution and morphological characteristics. The morphology of astrocytes and its response to diverse stimuli have been assessed in this mouse strain [ [25] , [26] , [27] , [28] , [29] ]. Because GFP is widely distributed in this transgenic strain, the astrocyte morphology can be characterized on different levels: from the number of main branches to the array of their small processes.…”

Roadbumps at the Crossroads of Integrating Behavioral and In Vitro Approaches for Neurotoxicity Assessment

“…Like human neurological exams, rodent observational batteries often serve as a first-tier test to identify “an effect.” Examples include the Functional Observational Battery ( US EPA, 1994b ; Moser and Kallman, 2018 ; Gauvin, 2021 ) and the SmithKline, Harwell, Imperial College, Royal Hospital, Phenotype Assessment (SHIRPA) ( Rogers et al, 2001 ; Lalonde et al, 2021 ). Additional batteries have been developed for assessing vestibular dysfunction ( Maroto et al, 2021 ), various genetic manipulations ( Brown et al, 2000 ), and neonatal function ( Fox, 1965 ; Brown et al, 2000 ; Feather-Schussler and Ferguson, 2016 ; Soria-Ortiz et al, 2021 ).…”