PT  - JOURNAL ARTICLE
AU  - Jose Luis Olmos-Serrano
AU  - Scott M. Paluszkiewicz
AU  - Brandon S. Martin
AU  - Walter E. Kaufmann
AU  - Joshua G. Corbin
AU  - Molly M. Huntsman
TI  - Defective GABAergic Neurotransmission and Pharmacological Rescue of Neuronal Hyperexcitability in the Amygdala in a Mouse Model of Fragile X Syndrome
AID  - 10.1523/JNEUROSCI.1714-10.2010
DP  - 2010 Jul 21
TA  - The Journal of Neuroscience
PG  - 9929--9938
VI  - 30
IP  - 29
4099  - http://www.jneurosci.org/content/30/29/9929.short
4100  - http://www.jneurosci.org/content/30/29/9929.full
SO  - J. Neurosci.2010 Jul 21; 30
AB  - 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 potential-dependent 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.