Abstract
GABAergic neurotransmission is highly plastic, undergoing dynamic alterations in response to changes in the environment, such as following both acute and chronic stress. Stress-induced plasticity of GABAergic inhibition is thought to contribute to changes in neuronal excitability associated with stress, which is particularly relevant for stress-related disorders and seizure susceptibility. Here we review the literature demonstrating several mechanisms altering GABAergic inhibition associated with stress, including brain region-specific alterations in GABAA receptor (GABAAR) subunit expression, changes in chloride homeostasis, and plasticity at GABAergic synapses. Alterations in the expression of specific GABAAR subunits have been documented in multiple brain regions associated with acute or chronic stress. In addition, recent work demonstrates stress-induced alterations in GABAergic inhibition resulting from plasticity in intracellular chloride levels. Acute and chronic stress-induced dephosphorylation and downregulation of the K+/Cl− co-transporter, KCC2, has been implicated in compromising GABAergic control of corticotropin-releasing hormone (CRH) neurons necessary for mounting the physiological response to stress. Acute stress also unmasks the capacity for both long-term potentiation and long-term depression, in distinct temporal windows, at GABAergic synapses on parvocellular neuroendocrine cells (PNCs) in the paraventricular nucleus (PVN) of the hypothalamus. This review highlights the complexity in the plasticity of GABAergic neurotransmission associated with stress and the relationship to neuronal excitability, including alterations in GABAAR expression, synaptic plasticity at GABAergic synapses, and changes in chloride homeostasis.
Highlights
GABAergic neurotransmission is highly plastic, undergoing dynamic alterations in response to changes in the environment, such as following both acute and chronic stress
Alterations in neuronal excitability and seizure susceptibility associated with stress have largely been attributed to changes in GABAergic inhibition
Recent evidence pointing to synaptic plasticity at GABAergic synapses and alterations in intracellular chloride levels resulting in compromised GABAergic inhibition following stress is highlighted
Summary
(Maggio and Segal, 2012), suggesting the involvement of multiple pathways regulating excitability in response to acute stress These data clearly demonstrate the anticonvulsant effects of acute stress, which is contrary to the notion that stress is associated with increased seizure susceptibility and is a trigger for seizures in patients with epilepsy (Minter, 1979) (for review see Maguire and Salpekar, 2013). Fewer follow up studies have focused on changes in specific GABAAR subtypes in specific brain regions and the impact on GABAergic inhibition Many of these studies have focused on stress-induced changes in GABA in the hippocampus in relation to changes in neuronal excitability (for review see Joels, 2009); recent interest has focused on the role of GABA within the stress neurocircuitry (for review see Gunn et al, 2011), the PVN of the hypothalamus.
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