Inhibitory Neurotransmission in the Fmr1 Knockout Mouse Model of Fragile X Syndrome: Region- and Circuit-specific Deficits

Fragile X Syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, sensory hypersensitivity, and high incidences of autism spectrum disorders (ASD) and epilepsy. These phenotypes are suggestive of defects in neural circuit development and imbalances in excitatory glutamatergic and inhibitory GABAergic neurotransmission in a number of brain regions. While alterations in excitatory synapse function and plasticity are well-established in Fmr1 knockout (KO) mouse models of FXS, considerably less is known about the state of inhibitory neurotransmission. In order to address the question of inhibitory dysfunction in FXS, we conducted electrophysiological studies of synaptic inhibition in Fmr1 KO mice in two highly relevant brain regions: the basolateral (BL) nucleus of the amygdala and primary somatosensory cortex. The studies described herein reveal profound, region-specific deficits in inhibitory neurotransmission. The Fmr1 KO BL amygdala is characterized by a pronounced reduction in synaptic inhibition onto excitatory projection neurons that is largely suggestive of presynaptic dysfunction. We observe decreases in the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), decreased GAD levels and vesicular GABA content, reduced inhibitory synapse number and strength, and increased projection neuron excitability. These inhibitory deficits are proposed to contribute to amygdala dysfunction in FXS. In experiments conducted in layer II/III of primary somatosensory cortex, iii we observe impaired activation of a specific inhibitory interneuron subtype, the low-threshold-spiking (LTS) neuron in Fmr1 KO mice, which results in dampened synaptic inhibition. Furthermore, paired recordings from layer II/III pyramidal neurons reveal reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to LTS neuron activation, indicating a weakened LTS interneuron network in Fmr1 KO mice, and providing a cellular link to altered cortical network function in line with the FXS phenotype. Together, these findings in the BL amygdala and somatosensory cortex reveal prominent inhibitory deficits in two brain regions that are central to the FXS phenotype, and provide novel evidence for the GABAergic system as an important target in understanding the etiology – and potential pharmacological approaches for treatment – of FXS. iv ACKNOWLEDGEMENTS