METABOTROPIC GLUTAMATE RECEPTORS IN SYNAPSES AND ASTROCYTES OF A MOUSE MODEL OF FRAGILE X SYNDROME DURING AGING

Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism, resulting from the loss of fragile X messenger ribonucleoprotein 1 (FMRP) and characterized by altered synaptic plasticity and cellular dysfunction. Metabotropic glutamate (mGlu) receptors are key modulators of excitatory neurotransmission and have been implicated in FXS pathophysiology, particularly mGlu5 signalling, whereas the contribution of other mGlu receptors remains largely unexplored despite their relevance in cognitive disorders. The aim of this study was to characterize age-dependent alterations of mGlu receptor subtypes in synaptic and astrocytic compartments of the Fmr1 knockout (KO) mouse model. Expression of mGlu5, mGlu3 and mGlu7 receptors was analysed in cortical synaptosomes from young adult and aged mice and in astrocytes isolated by magnetic-activated cell sorting (MACS), while functional consequences were investigated in cultured mouse astrocytes. We found that mGlu5 and mGlu3 receptors are differently expressed in MACS-isolated astrocytes and cortical synaptosomes from young adult and aged Fmr1 KO mice, whereas mGlu7 expression was unchanged compared with WT controls. Activation of mGlu3 receptors affected stress granule formation in Fmr1 KO astrocytes, in line with its protective involvement in cellular stress responses and was associated with a modulation of stress-induced inflammatory signalling, as suggested by ELISA analyses of cytokines and growth factors. These findings highlight mGlu receptor subtype-specific alterations in synapses and astrocytes in FXS and support mGlu3 and mGlu5 as potential targets for modulating astrocytic dysfunction and age-related disease progression.
Funded by European Union-Next Generation EU, Mission 4, Component 2, CUP E63C22002170007
FOE-2022 INVAT