Aberrant astrocyte signalling during hippocampal development in the Fmr1-knockout mouse model

Fragile-X Syndrome (FXS) is the leading genetic cause of intellectual disability among children and results from the loss of fragile X messenger ribonucleoprotein (FMRP), an mRNA-regulating protein. The development of the hippocampal region has been of great interest in FXS research due to its primary involvement in learning and memory, with much of the work focused on the intrinsic dysfunction of neurons within the circuit. The potentially pathological roles of glial cells, such as astrocytes, in the FXS hippocampus remain largely unknown, as do the molecular mechanisms that underlie them. Work in the Fmr1 -/- (knockout, KO) mouse model highlighted the purinergic signalling system as a glial signalling pathway that was dysregulated in the cortex. Specifically, the P2Y2 receptor was shown to be upregulated on cortical astrocytes, but it was unknown if it was affected in the hippocampus. Our study sought to begin that examination. Here, we found that the P2Y2 receptor was increased in expression at postnatal day 21 in the Fmr1 -KO hippocampus but not at other time points. We identified that astrocytes throughout the hippocampus largely accounted for the source of this upregulation. Measuring the calcium response in WT and Fmr1-KOastrocytes in vitro showed that a greater proportion of Fmr1 -KO astrocytes responded to P2Y2 agonism than WT, and that the calcium responses were slightly larger and longer, with no differences in the peak calcium change. This study demonstrates a developmental dysfunction of P2Y2 signalling in the Fmr1 -KO hippocampus and emphasizes the contribution of glial-mediated pathology in FXS.