Glial Activation in a Mouse Model of Fragile X Syndrome

Background: Fragile X Syndrome is a neurodevelopmental disorder caused by a mutation in the X-linked FMR1 gene that results in complete loss of the protein product FMRP. Approximately 25% of individuals with Fragile X meet the diagnostic criteria for Autism Spectrum Disorders (ASDs).  Postmortem studies have identified neuroinflammation and glial activation in the brains of individuals with idiopathic ASDs and studies suggest a similar pathology may be present in Fragile X Syndrome. Whether neuroinflammatory changes are pathogenic or protective in these disorders remains to be determined.

Objectives: To characterize neuroinflammatory changes and glial activation in the cerebellum of a mouse model of Fragile X Syndrome (FMR1 KO mice) at various developmental time points.

Methods: Quantitative immunohistochemistry and Western blotting were used to compare the expression of glial markers in wild-type and FMR1 knockout mice at several developmental time points.

Results: Expression of the astrocyte marker GFAP was significantly increased in the cerebellum of FMR1 knockout mice. In females, this difference was evident as early as postnatal day 30 (PND30) and persisted into adulthood. Increased GFAP expression was detected in male FMR1 KO mice in adulthood, but not at PND30. No differences in expression were detected at PND7 in either sex.  Expression of S100B, which stains Bergmann Glia, was significantly increased in adult FMR1 KO mice, but was not different at earlier ages. CD68 expression (a marker of microglia) was not different in FMR1 KO cerebellum at PND7 or in adults.

Conclusions: Upregulation of glial markers in the cerebellum of a mouse model of Fragile X Syndrome indicate astrogliosis as early as one month after birth that persists into adulthood.