The basolateral amygdala γ-aminobutyric acidergic system in health and disease

Abstract

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. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or development of seizure activity. This Review discusses the anatomy, development, and physiology of the GABAergic system in the BLA and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. 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.

Keywords: Alzheimer's disease; GABA; anxiety; autism; basolateral amygdala; epilepsy.

Figure 1. Modulation of GABAergic Inhibitory Synaptic Transmission in the BLA

(A) Schematic representation of GABAergic projections from the prefrontal cortex (PFC) and glutamatergic projections from the thalamus. In addition, GABAergic interneurons in the BLA receive cholinergic projections from the substantia innominate (SN) and ventral pallidum (VP), dopaminergic projections from the ventral tegmental area (VTN) and substantia nigra (SN), noradrenergic projections from the locus coeruleus (LC) and nucleus of the solitary tract (NTS), and serotonergic projections from the dorsal raphé nucleus (DRN). (B) Schematic representation of receptors modulating GABAergic inhibitory synaptic transmission in the BLA. Postsynaptic (1A) M2-mAChRs and (2A) GABA_B receptors hyperpolarize GABAergic interneurons by reducing voltage gated Ca²⁺ channels and increasing K⁺ channel conductance. (1B) M1-mAChRs increase excitability (though primarily expressed on principal neurons) by suppressing several K⁺ currents and increasing voltage gated Ca²⁺ conductance. (2B) Activation of presynaptic GABA_B receptors inhibit neurotransmitter release on both excitatory and inhibitory synapses by inhibiting voltage-gated Ca²⁺ channels and possibly by interacting with vesicular release machinery.(3A) Activation of postsynaptic NMDA or AMPA receptors on interneurons increases excitability. (3B) Activation of GluK1-containing kainate receptors depolarize interneurons by increasing the presynaptic release of GABA or increasing excitability via activation of postsynaptic GluK1 receptors. (4) Activation of α₇-nAChRs and/or α₄β₂ nAChRs presynaptically modulate GABA release or regulate neuronal activity by their position on interneurons. (5A) Dopaminergic projections activate postsynaptic D1 receptors, which increase excitability by reducing slowly inactivating K⁺ currents while D2 (5B) receptors reduce presynaptic release of GABA. (6) Activation of ASIC1A receptors increase interneuronal excitability. Postsynaptically, activation of 5-HT₂(7A) and 5-HT_3A(7B) receptors increase interneuronal excitability via an increase in intracellular Ca²⁺ concentrations or increasing the interneuronal excitability, respectively. (7C) Activation of presynaptic 5-HT_1A receptors reduce quantal release and increases hyperpolarization. (8) Activation of α1 and α2 receptors depolarize interneurons, subsequently increasing action potential firing and enhancing inhibitory synaptic transmission. (9) Activation of CB1 receptors on CCK interneurons reduces presynaptic release by inhibiting voltage gated Ca²⁺ channels and activating voltage gated K⁺ channel.