UC Riverside

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the leading known genetic cause of autism spectrum disorder (ASD). Approximately 96% of individuals with ASD and FXS experience improper processing of sensory stimuli. Possible mechanisms attributed to this hyperarousal state include altered excitatory and inhibitory balance and impaired synaptic development. How these developmental changes impair sensory processing, neural responses and functions remain unclear. The major goal of my dissertation project is to identify the developmental mechanisms underlying the pathophysiology of FXS. Our previous studies have shown that elevated levels of Matrix Metalloproteinase-9 (MMP-9) contribute to the hyper-responsiveness of auditory cortex in Fmr1 KO mice by affecting perineuronal net (PNN) formation around parvalbumin (PV)-expressing inhibitory interneurons. Abnormal development of PV neurons most likely contributes to abnormal electroencephalography (EEG)-based phenotypes of auditory hypersensitivity in the Fmr1 KO mice that are remarkably similar to those seen in humans with FXS. However, how the expression of Fmr1 in different cell types shapes normal cortical responses during circuit development is not known.Therefore, I investigated whether the disruption of communication between excitatory neurons and inhibitory PV cells was sufficient to trigger abnormal phenotypes using several mouse models. In the first part of this study, cell-specific deletion of Fmr1 was achieved in cortical excitatory neurons during early embryonic development. I demonstrated that embryonic deletion of Fmr1 from cortical excitatory neurons did indeed trigger PV cell loss, abnormal cortical responses, and behavioral phenotypes in the auditory cortex of Fmr1 KO mice. In the second part of this study, I examined whether conditional deletion (cOFF) or re-expression (cON) of Fmr1 in excitatory neurons during the critical postnatal day (P)14-P21 period of PV cell development is sufficient to trigger or prevent abnormal phenotypes. Our results indicate that postnatal deletion or re-expression of FMRP in excitatory neurons is sufficient to elicit or ameliorate structural and functional cortical deficits as well as abnormal behavioral phenotypes in mice, informing future gene re-expression studies about appropriate treatment window and providing a new insight into the mechanism of cortical circuit dysfunctions in FXS. Lastly, with the discovery of FMRP in astrocytes, coupled with a role of astrocytes in synaptic function and inhibition in particular, it is possible that astrocytes contribute, in some capacity, to the impaired inhibition and circuit hyperexcitability seen in FXS. Therefore, in the third part of this study, I aimed to determine whether astrocyte-specific deletion of Fmr1 during critical developmental period of inhibitory circuit maturation would alter GABAergic signaling and PV cell development leading to cortical hyperexcitability and behavioral alterations. Our results demonstrate a profound role of astrocytic FMRP in the development of inhibitory circuits and shaping normal inhibitory responses.