Ionotropic and metabotropic kainate receptor signaling regulates Cl− homeostasis and GABAergic inhibition

Key Points

KCC2 plays a critical role in regulating chloride homeostasis, which is essential for hyperpolarizing inhibition in the mature nervous system. KCC2 interacts with many proteins involved in excitatory neurotransmission, including the GluK2 subunit of the kainate receptor (KAR). We show that activation of KARs hyperpolarizes the reversal potential for GABA (E_GABA) through both ionotropic and metabotropic signalling mechanisms. KCC2 is required for the metabotropic KAR‐mediated regulation of E_GABA, but ionotropic KAR signalling can hyperpolarize E_GABA independent of KCC2 transporter function. The KAR‐mediated hyperpolarization of E_GABA is absent in the GluK1/2^−/− mouse and is independent of zinc release from mossy fibre terminals. The ability of KARs to regulate KCC2 function may have implications in diseases with disrupted excitation: inhibition balance, such as epilepsy, neuropathic pain, autism spectrum disorders, and down syndrome.

Abstract

Potassium‐chloride co‐transporter 2 (KCC2) plays a critical role in the regulation of chloride (Cl⁻) homeostasis within mature neurons. KCC2 is a secondarily active transporter that extrudes Cl⁻ from the neuron, which maintains a low intracellular Cl⁻ concentration [Cl⁻]. This results in a hyperpolarized reversal potential of GABA (E_GABA), which is required for fast synaptic inhibition in the mature central nervous system. KCC2 also plays a structural role in dendritic spines and at excitatory synapses, and interacts with 'excitatory' proteins, including the GluK2 subunit of kainate receptors (KARs). KARs are glutamate receptors that display both ionotropic and metabotropic signalling. We show that activating KARs in the hippocampus hyperpolarizes E_GABA, thus strengthening inhibition. This hyperpolarization occurs through both ionotropic and metabotropic KAR signalling in the CA3 region, is absent in the GluK1/2^−/− mouse, and is independent of zinc release from mossy fibre terminals. The metabotropic signalling mechanism is dependent on KCC2, but the ionotropic signalling mechanism produces a hyperpolarization of E_GABA even in the absence of KCC2 transporter function. These results demonstrate a novel functional interaction between a glutamate receptor and KCC2, a transporter critical for maintaining inhibition, suggesting that the KAR: KCC2 complex may play an important role in excitatory: inhibitory (E:I) balance in the hippocampus. Additionally, the ability of KARs to regulate chloride homeostasis independently of KCC2 suggests that KAR signalling can regulate inhibition through multiple mechanisms. Activation of kainate‐type glutamate receptors could serve as an important mechanism for increasing the strength of inhibition during periods of strong glutamatergic activity.

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