Astroglial FMRP modulates synaptic signaling and behavior phenotypes in FXS mouse model

Abstract

Fragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron‐centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor‐skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS‐related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR‐mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re‐expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS‐related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.

Astroglial FMRP deficiency cell-autonomously up-regulates miR-128 and disrupts developmental astroglial mGluR5 signaling

“…It is well established that astroglial GLT1-mediated glutamate uptake and PAP coverage of synapses actively and significantly impact synaptic transmission (35). Thus, premature decrease of astroglial mGluR5 by FMRP deficiency-induced up-regulation of miR-128-3p would alter key astroglial functions from gliotransmission to glutamate uptake and synaptic coverage, contributing to altered synaptic signaling and enhanced neuronal excitability in FXS conditions, as we recently observed in synaptic signaling and behaviors of astroglial Fmr1 cKO mice (18,36). It is important to note that while our results define a miRbased molecular pathway in down-regulating mGluR5 in FMRPdeficient astroglia, mGluR1/5 expression is not altered in FMRP-deficient neurons despite the observation of enhanced group I mGluR-mediated synaptic plasticity in Fmr1 KO mice (37,38).…”

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

“…By using conditional knockout (cKO) and conditional restored (cON) mice in astrocytes, they find that loss of FMRP results in cortical hyperactivity, increased locomotor activity, reduced social novelty preference and deficit of memory acquisition. Reactivation of the astrocyte Fmr1 rescues these phenotypes (Jin et al, 2021).…”

Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits

“…Within each experiment, each mouse was imaged and analyzed on 2-5 independent brain sections (technical replicates), that were then averaged per mouse. Quantification of colocalized puncta was performed as previously described using the Imaris software (Bitplane) spots tool and colocalization algorithm 10,31,42 . Spot sizes were set to 0.35 um for Vgat and Vglut1 puncta and 0.3 um for Gephyrin and PSD95 puncta with a center-to-center colocalization distance of 0.6 um.…”

“…9 Astrocyte-specific Fmr1 KO and re-expression studies highlight a role for astrocytes in some Fmr1 KO cortical excitability and behavioral phenotypes. 10…”