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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 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.

SUBMITTER: Olmos-Serrano JL

PROVIDER: S-EPMC2948869 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome.

Olmos-Serrano Jose Luis JL Paluszkiewicz Scott M SM Martin Brandon S BS Kaufmann Walter E WE Corbin Joshua G JG Huntsman Molly M MM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100701 29

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 in ...[more]

PMID: 20660275

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Project description:Impaired mitochondrial function and aberrant neuronal network activity are believed to be early events in the pathogenesis of Alzheimer's disease (AD), but how mitochondrial alterations contribute to aberrant activity in neuronal circuits is unknown. In this study, we examined the function of mitochondrial protein deacetylase sirtuin 3 (SIRT3) in the pathogenesis of AD. Compared with AppPs1 mice, Sirt3-haploinsufficient AppPs1 mice (Sirt3+/-AppPs1) exhibit early epileptiform EEG activity and seizure. Both male and female Sirt3+/-AppPs1 mice were observed to die prematurely before 5 months of age. When comparing male mice among different genotypes, Sirt3 haploinsufficiency renders GABAergic interneurons in the cerebral cortex vulnerable to degeneration and associated neuronal network hyperexcitability. Feeding Sirt3+/-AppPs1 AD mice with a ketone ester-rich diet increases SIRT3 expression and prevents seizure-related death and the degeneration of GABAergic neurons, indicating that the aggravated GABAergic neuron loss and neuronal network hyperexcitability in Sirt3+/-AppPs1 mice are caused by SIRT3 reduction and can be rescued by increase of SIRT3 expression. Consistent with a protective role in AD, SIRT3 levels are reduced in association with cerebral cortical A? pathology in AD patients. In summary, SIRT3 preserves GABAergic interneurons and protects cerebral circuits against hyperexcitability, and this neuroprotective mechanism can be bolstered by dietary ketone esters.SIGNIFICANCE STATEMENT GABAergic neurons provide the main inhibitory control of neuronal activity in the brain. By preserving mitochondrial function, SIRT3 protects parvalbumin and calretinin interneurons against A?-associated dysfunction and degeneration in AppPs1 Alzheimer's disease mice, thus restraining neuronal network hyperactivity. The neuronal network dysfunction that occurs in Alzheimer's disease can be partially reversed by physiological, dietary, and pharmacological interventions to increase SIRT3 expression and enhance the functionality of GABAergic interneurons.

Dataset Information

Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome.

Publications

Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome.

Similar Datasets

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