The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2‐q13)

Abstract

Fragile X syndrome (FXS), caused by lack of fragile X mental retardation protein (FMRP), is associated with a high prevalence of autism. The deficit of FMRP reported in idiopathic autism suggests a mechanistic overlap between FXS and autism. The overall goal of this study is to detect neuropathological commonalities of FMRP deficits in the brains of people with idiopathic autism and with syndromic autism caused by dup15q11.2-q13 (dup15). This study tests the hypothesis based on our preliminary data that both idiopathic and syndromic autism are associated with brain region-specific deficits of neuronal FMRP and structural changes of the affected neurons. This immunocytochemical study revealed neuronal FMRP deficits and shrinkage of deficient neurons in the cerebral cortex, subcortical structures, and cerebellum in subjects with idiopathic and dup(15)/autism. Neuronal FMRP deficit coexists with surprising infiltration of the brains of autistic children and adults with FMRP-positive astrocytes known to be typical only for the fetal and short postnatal periods. In the examined autistic subjects, these astrocytes selectively infiltrate the border between white and gray matter in the cerebral and cerebellar cortex, the molecular layer of the cortex, part of the amygdala and thalamus, central cerebellar white matter, and dentate nucleus. Astrocyte pathology results in an additional local loss of FMRP in neurons and their shrinkage. Neuronal deficit of FMRP and shrinkage of affected neurons in structures free of FMRP-positive astrocytes and regions infiltrated with FMRP-expressing astrocytes appear to reflect mechanistic, neuropathological, and functional commonalities of FMRP abnormalities in FXS and autism spectrum disorder. Autism Res 2018, 11: 1316-1331. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Immunocytochemistry reveals a deficit of fragile X mental retardation protein (FMRP) in neurons of cortical and subcortical brain structures but increased FMRP expression in astrocytes infiltrating gray and white matter. The detected shrinkage of FMRP-deficient neurons may provide a mechanistic explanation of reported neuronal structural and functional changes in autism. This study contributes to growing evidence of mechanistic commonalities between fragile X syndrome and autism spectrum disorder.

Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions

“…However, the more immediate question, and the focus of the current study, concerns the relationship between cognitive ability and FMRP levels, irrespective of CGG-repeat size: how much FMRP is necessary for borderline to average intellectual functioning? The relevance of this question extends beyond the fragile X-associated disorders to other forms of neurodevelopmental and neuropsychiatric dysfunction, as exemplified by lowered FMRP levels in the brains of those with autism/ASD [70–72] and major psychiatric disorders, including depression and schizophrenia [73, 74].…”

Pathology and Astrocytes in Autism

“… 38 They also have crucial roles in neurodevelopment including in neurogenesis, neuronal migration, and synaptic plasticity. 39 , 40 In addition, with pre- and postsynaptic neurons, perisynaptic astrocytes form tripartite synapses to modulate synaptic transmission. 41 Together with microglia, astrocytes are regulators of the inflammatory responses.…”