Fragile X syndrome: the GABAergic system and circuit dysfunction

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, sensory hypersensitivity, and high incidences of autism spectrum disorders and epilepsy. These phenotypes are suggestive of defects in neural circuit development and imbalances in excitatory glutamatergic and inhibitory GABAergic neurotransmission. While alterations in excitatory synapse function and plasticity are well-established in Fmr1 knockout (KO) mouse models of FXS, a number of recent electrophysiological and molecular studies now identify prominent defects in inhibitory GABAergic transmission in behaviorally relevant forebrain regions such as the amygdala, cortex, and hippocampus. In this review, we summarize evidence for GABAergic system dysfunction in FXS patients and Fmr1 KO mouse models alike. We then discuss some of the known developmental roles of GABAergic signaling, as well as the development and refinement of GABAergic synapses as a framework for understanding potential causes of mature circuit dysfunction. Finally, we highlight the GABAergic system as a relevant target for the treatment of FXS.

Fig. 1

Several GABAergic synapse components exhibit altered expression in the Fmr1 KO mouse model of FXS. Numbers identify key synaptic proteins disrupted in Fmr1 KOs, including GABA_A receptors, enzymes involved in GABA production and catabolism (GAD, SSADH, GABA-T) and GAT (inset legend; table 1).

Fig. 2

Alterations in inhibitory neurotransmission in the Fmr1 KO mouse brain are pervasive, but region-specific. Regional inhibitory deficits are associated with a number of common FXS phenotypes (inset table). Affected regions include the basolateral amygdala, cerebral cortex, striatum and hippocampus/subiculum. Color coding in the illustration corresponds to the adjacent inset table.

Fig. 3

Potential pharmacological targets for the treatment of FXS. Numbers identify loci of action of pharmacological compounds targeting components of the GABAergic system (inset legend; table 2). Note: The presumed actions of arbaclofen (4) are illustrated as predominately postsynaptic, since presynaptic modulation is expected to reduce GABA release via a reduction in voltage-dependent calcium influx. However, since glutamatergic terminals also express presynaptic GABA_B receptors, additional beneficial actions of arbaclofen could also lie in the reduction of glutamate release from excitatory synapses.