Journal of neuroscience research
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The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of γ-aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, an alteration in GABAA receptor activation, or a dysregulation of mechanisms that modulate BLA GABAergic inhibition. ⋯ We highlight how alterations in various neurotransmitter receptors, including the acid-sensing ion channel 1a, cannabinoid receptor 1, and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affect inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/fragile X syndrome) and neurodegenerative (Alzheimer's disease) diseases and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases.
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Alterations in the ratio of excitatory to inhibitory transmission are emerging as a common component of many nervous system disorders, including autism spectrum disorders (ASDs). Tonic γ-aminobutyric acidergic (GABAergic) transmission provided by peri- and extrasynaptic GABA type A (GABAA ) receptors powerfully controls neuronal excitability and plasticity and, therefore, provides a rational therapeutic target for normalizing hyperexcitable networks across a variety of disorders, including ASDs. Our previous studies revealed tonic GABAergic deficits in principal excitatory neurons in the basolateral amygdala (BLA) in the Fmr1(-/y) knockout (KO) mouse model fragile X syndrome. ⋯ Furthermore, at submicromolar concentrations (≤1 μM), SGE-872 is selective for tonic, extrasynaptic α4β3δ-containing GABAA receptors over typical synaptic α1β2γ2 receptors. We further find that SGE-872 strikingly rescues the tonic GABAergic transmission deficit in principal excitatory neurons in the Fmr1(-/y) KO BLA, a structure heavily implicated in the neuropathology of ASDs. Therefore, the potent and selective action of SGE-872 on tonic GABAA receptors containing α4 subunits may represent a novel and highly useful therapeutic avenue for ASDs and related disorders involving hyperexcitability of neuronal networks.