Defective GABAergic Neurotransmission and Pharmacological Rescue of Neuronal Hyperexcitability in the Amygdala in a Mouse Model of Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by variable cognitive impairment and behavioral disturbances such as exaggerated fear, anxiety and gaze avoidance. Consistent with this, findings from human brain imaging studies suggest dysfunction of the amygdala. Underlying alterations in amygdala synaptic function in the Fmr1 knock-out (KO) mouse model of FXS, however, remain largely unexplored. Utilizing a combination of approaches, we uncover profound alterations in inhibitory neurotransmission in the amygdala of Fmr1 KO mice. We demonstrate a dramatic reduction in the frequency and amplitude of phasic IPSCs, tonic inhibitory currents, as well as in the number of inhibitory synapses in Fmr1 KO mice. Furthermore, we observe significant alterations in GABA availability, both intracellularly and at the synaptic cleft. Together, these findings identify abnormalities in basal and action potentialdependent inhibitory neurotransmission. Additionally, we reveal a significant neuronal hyperexcitability in principal neurons of the amygdala in Fmr1 KO mice, which is strikingly rescued by pharmacological augmentation of tonic inhibitory tone using the GABA agonist gaboxadol (THIP). Thus, our study reveals relevant inhibitory synaptic abnormalities in the amygdala in the Fmr1 KO brain and supports the notion that pharmacological approaches targeting the GABAergic system may be a viable therapeutic approach toward correcting amygdala-based symptoms in FXS.

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…In contrast, reduced tonic GABA A currents were observed in the subiculum of Fmr1 knockout mice, coupled with the downregulation of α5 and δ protein expression (Curia et al, 2008). Similarly, significant reductions in the frequency/amplitude of phasic IPSCs and a decrease in tonic inhibitory currents were observed in the basalateral nucleus of the amygdala of Fmr1 knockout mice (Olmos-Serrano et al, 2010). Additionally, a down-regulation of GAD65/67 expression and reduced GABA concentration observed at the synaptic cleft was indicative of a presynaptic defect in GABAergic transmission in Fmr1 knockout mice.…”

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

“…This impairment could be a consequence of excessive protein synthesis during development or a parallel pathophysiologic process. In any case, some fragile X phenotypes that respond to mGluR5 inhibitors have also been ameliorated by administering compounds that activate GABA receptors, both in the mouse (Pacey et al 2009;Olmos-Serrano et al 2010) and the fly (Chang et al 2008) models. The selective GABA B receptor agonist R-baclofen has recently attracted interest as a potential therapeutic in FXS, because it both decreases neuronal excitability via activation of dendritic potassium conductances and directly inhibits the synaptic release of glutamate (and therefore, indirectly, mGluR5 activation) (Kohl and Paulsen 2010).…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…On the other hand, it could be a secondary effect of dysregulated mGlu 1/5 -dependent signaling, because these two receptors were shown to crosstalk in several different brain areas (Hirono et al, 2001;Deng et al, 2010;Kolaj and Renaud, 2010). The exact mechanisms of reduced GABA-mediated signaling in FXS are currently unclear; nevertheless, results from animal studies and clinical trials suggest that GABA agonists are suitable to treat FXS-associated symptoms (Chang et al, 2008;Heulens et al, 2010;Olmos-Serrano et al, 2010).…”