Author : Alexia Gene
Publisher :
Page : pages
File Size : 32,22 MB
Release : 2022
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ISBN :
"Fast inhibitory neurotransmission in the brain is predominately controlled by GABAA receptors (GABARs) which act to regulate neuronal excitability. Abnormal signaling and plasticity of GABAergic neurons have been implicated in many CNS diseases, most relevant is the neurodevelopmental disorder Fragile X Syndrome (FXS). In FXS, regulation of the brain's excitatory-inhibitory balance is extremely important, since one of the pivotal characteristics is an increase in neuronal excitability. Although it has been suggested that the neurophysiology of hyperexcitability is partly due to a GABAergic hypofunction, there is insufficient evidence to support this theory. Therefore, experiments were designed here to test the hypothesis that hyperexcitability in FXS is the result of defective GABAergic transmission. My experimental plan was divided into two primary objectives, first I compared GABAergic signaling and plasticity in the cerebellum of both wild-type (WT) and FXS mice (Fmr1KO mice). The strengthening of synaptic connectivity was assessed using activity-dependent stimulation of GABAergic synapses on molecular layer interneurons (MLIs) in the cerebellum to tease apart the GABAR subtypes that are involved. My data demonstrates that WT MLIs undergo [alpha]3-mediated inhibitory long-term potentiation (iLTP) that is reliant on nitric oxide (NO) and cyclic guanosine monophosphate (cGMP), which can be observed by an increase in synapse connectivity. Unexpectedly, MLIs are also subject to [alpha]1-mediated inhibitory long-term depression (iLTD) that is dependent on group 1 metabotropic glutamate receptors (Gp 1 mGluRs). In contrast, Fmr1KO mice completely lack [alpha]3- mediated iLTP and possess an enhanced iLTD for both [alpha]1 and [alpha]3 synapses. Thus, we used a combinational therapeutic strategy to block Gp1 mGluRs, while simultaneously activating the pathway implicated in GABAergic plasticity to successfully rescue the enhanced iLTD and restore iLTP in Fmr1KO mice. Overall, these findings provide a novel mechanism for understanding synaptic connectivity in FXS while also describing a combination of small molecule therapeutics to correct deficits in synaptic plasticity"--