Glial cells are affected more than interneurons by the loss of Engrailed 2 gene in the mouse cerebellum

Abstract

Glial cells play a pivotal role in the inflammatory processes, which are common features of several neurodevelopmental and neurodegenerative disorders. Their major role in modulating neuroinflammation underscores their significance in these conditions. Engrailed‐2 knockout mice (En2−/−) are considered a valuable model for autism spectrum disorder (ASD) due to their distinctive neuroanatomical and behavioral traits. Given the higher prevalence of ASD in males, our objective was to investigate glial and interneuron alterations in the cerebellum of En2−/− mice compared with wild‐type (WT) mice in both sexes. We employed immunohistochemical analysis to assess cell density for all cell types studied and analyzed the area (A) and shape factor (SF) of microglia cell bodies. Our findings revealed the following: (a) In WT mice, the density of microglia and astrocytes was higher in females than in males, while interneuron density was lower in females. Notably, in En2‐mutant mice, these differences between males and females were not present. (b) In both male and female En2−/− mice, astrocyte density exceeded that in WT mice, with microglia density being greater only in females. (c) In WT females, microglia cell bodies exhibited a larger area and a lower shape factor compared to WT males. Remarkably, the En2 mutation did not appear to influence these sex‐related differences. (d) In both male and female En2−/− mice, we observed a consistent pattern: microglia cell bodies displayed a larger area and a smaller shape factor. Given the ongoing debate surrounding the roles of glia and sex‐related factors in ASD, our observations provide valuable insights into understanding how an ASD‐associated gene En2 affects specific cell types in the cerebellum.

Neuroplasticity of children in autism spectrum disorder

“…For example, Ash1L haploinsufficiency leads to defective synaptic pruning of neurons in the brain, triggering ASD-related behavioral deficits, and these abnormal behaviors are mediated by cortical circuits ( 24 ). Neuroinflammation and neuroimmunity also play an important role in this, Engrailed-2 knockout mice have an increased density of astrocytes in the brain and induce neuroinflammatory and neurodegenerative changes ( 145 ). ASD patients have a significant overexpression of histaminergic system-related genes in the brain and chronic neuroinflammation, which may be due to the mechanism that histaminergic system affects neuroinflammation by regulating microglial cell activation, cytokine release, and migration to influence neuroinflammation ( 146 ).…”