Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model

Abstract

Objective: Much evidence suggests that the subiculum plays a significant role in the regulation of epileptic activity. Lactate acts as a neuroprotective agent against many conditions that cause brain damage. During epileptic seizures, lactate formation reaches up to ~6 mmol/L in the brain. We investigated the effect of lactate on subicular pyramidal neurons after induction of epileptiform activity using 4-aminopyridine (4-AP-0Mg 2+ ) in an in vitro epilepsy model in rats. The signaling mechanism associated with the suppression of epileptiform discharges by lactate was also investigated. Methods: We used patch clamp electrophysiology recordings on rat subicular neurons of acute hippocampal slices. Immunohistochemistry was used for demonstrating the expression of hydroxycarboxylic acid receptor 1 (HCA1) in the subiculum. Results: Our study showed that application of 6 mmol/L lactate after induction of epileptiform activity reduced spike frequency (control 2.5 ± 1.23 Hz vs lactate 1.01 ± 0.91 Hz, P = .049) and hyperpolarized the subicular neurons (control −51.8 ± 1.9 mV vs lactate −57.2 ± 3.56 mV, P = .002) in whole cell patch-clamp experiments. After confirming the expression of HCA1 in subicular neurons, we demonstrated that lactate-mediated effect occurs via HCA1 by using its specific agonist. All values are mean ±SD. Electrophysiological recordings revealed the involvement of Gβγ and intracellular cAMP in the lactate-induced effect. Furthermore, current-clamp and voltage-clamp experiments showed that the G protein-coupled inwardly rectifying potassium (GIRK) channel blocker tertiapin-Q, negated the lactateinduced inhibitory effect, which confirmed that lactate application results in outward GIRK current. Significance: Our finding points toward the potential role of lactate as an anticonvulsant by showing lactate-induced suppression of epileptiform activity in subicular neurons. The study gives a different insight by suggesting importance of endogenous metabolite and associated signaling factors, which can aid in improving the present therapeutic approach for treating epilepsy.

Lactate induces synapse-specific potentiation on CA3 pyramidal cells of rat hippocampus

“…If this is the case, it remains to be demonstrated if lactate exerts dendritic modulation of potassium channels, as a plausible mechanism underlying the EPSP-to-spike coupling. On the other hand, a growing number of works demonstrated that lactate modulates multiple ion channels and modifies the firing discharge and intrinsic excitability [15,17,48,51]. Thus, it is reasonable to assume that lactate may exert specific actions on one synaptic input (RC) and simultaneously exert modulatory actions on the ionic conductances that shape the action potential discharge.…”

Lactic acid promotes metastatic niche formation in bone metastasis of colorectal cancer

“…Due to the Warburg effect, a process unique to cancer cells, LA can be produced and accumulate extensively in tumors [1]. It is currently thought that in addition to simply supplying energy, excessive LA performs other physiological functions, such as regulating immunity, metabolism and angiogenesis [2][3][4][5].…”

Metabolic Control of Epilepsy: A Promising Therapeutic Target for Epilepsy

“…Exogenous lactate may also act as an inhibitor in hippocampal neurons. According to a recent research, exogenous lactate induced outward currents mediated by G protein-gated inwardly rectifying potassium(GIRK) through activating GPR81, resulting in hyperpolarization and epileptiform firing decreasing in the subicular neurons of hippocampal slices ( Figure 2C) (84). Furthermore, lactate could regulate some ion channels by decreasing pH.…”

“…(B) Lactate over physiological levels acted as an inhibitor for cortical neurons a GPR81-mediated pathway(81)(82)(83). (C) Exogenous lactate (over physiological levels) induced an outward current mediated by G protein-gated inwardly rectifying potassium (GIRK) through activating GPR81, resulting in hyperpolarization and epileptiform firing decrease in the subicular neurons(84). (D) Lactate could regulate acid-sensing ion channel−1a (ASIC1a) by decreasing pH to Stimulate inhibitory neuronal excitation(85).…”