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.

Astrocytes regulate inhibition in Fragile X Syndrome

“…We found that postnatal Fmr1 deletion from astrocytes leads to increased GABA levels in astrocytes but decreased expression of synaptic GABAAR and PV levels. Previous studies have shown reduced expression of astroglial glutamate transporter GLT1 and impaired clearance of extracellular glutamate in astroglial Fmr1 cKO mice that may contribute to enhanced hyperexcitability 28,31,75 . However, whether astrocytic Fmr1 affects GABA-mediated signaling remains largely unexplored.…”

“…Fmr1 KO astrocytes are known to trigger FXS-like changes in WT excitatory neurons [28][29][30] . The enhanced excitability was also linked to reduced levels of glutamate transporter in FMRPdeficient astrocytes and reduced glutamate uptake by the astrocytes 28,31 . Whether astrocytes contribute to abnormal inhibitory cell development and circuit hyperexcitability by altering GABAergic signaling has not been investigated in FXS.…”

“…Fmr1 KO astrocytes are known to trigger FXS-specific changes in wild-type (WT) excitatory neurons [28][29][30] . The enhanced excitability was also linked to reduced expression of glutamate transporter in FMRP-deficient astrocytes and reduced glutamate uptake by the astrocytes 28,31 .…”

Cellular distribution of the Fragile X mental retardation protein in the inner ear: a developmental and comparative study in the mouse, rat, gerbil, and chicken

“…In this study, we identified cytoplasmic FMRP in satellite glial cells of both rodents and chickens as well as FMRP‐containing envelops surrounding AG neurons in chickens. In the brain, astrocyte‐specific loss of FMRP disrupts astrocytic mGluR5 signaling, alters neuronal dendritic and synaptic development, and contributes to cortical hyperexcitability (Jacobs et al., 2010, 2012; Jin et al., 2021; Men et al., 2020). Determining the significance of FMRP expression in satellite glial cells requires functional analyses.…”

Functionally Clustered mRNAs Are Distinctly Enriched at Cortical Astroglial Processes and Are Preferentially Affected by FMRP Deficiency

“…FMRP-deficient astroglia are capable of inducing abnormal dendritic morphology of WT hippocampal neurons in cocultures (Nimchinsky et al, 2001). Loss of FMRP in astroglia also disrupts astroglial mGluR5 signaling (Men et al, 2020) and reduces expression of the major astroglial glutamate transporter GLT1 and glutamate uptake in the cortex of Fmr1 KO mice (Higashimori et al, 2016), and exhibits several FXS-relevant behavior changes (Jin et al, 2021). As an RBP that is expressed in astroglia, whether FMRP is involved in regulating the localization and expression of mRNAs at astroglial processes is unknown.…”