Abstracts

Lactate, once viewed solely as a glycolytic byproduct, has emerged as a key play in brain metabolism and signaling. During seizures, increased glycolytic activity leads to accumulation of lactate. In Increased glycolysis, pyruvate is formed and converted to lactate through lactate dehydrogenase (LDH). However, recent evidence reveals that lactate also modulates neuronal excitability via HCAR1, a G-protein coupled receptor expressed in the hippocampus, cortex, and cerebellum.

 This dual role is especially relevant in epilepsy, where hyperexcitability and metabolic dysregulation coexist. Lactate may exacerbate seizures by fueling hyperactive networks while also downregulating excitability via HCAR1. Timing, concentration, and cellular context of lactate signaling could all influence lactate’s role in the brain. It is essential to distinguish to fully understand how lactate shapes neuronal activity.

The role of lactate in the CA1 has been largely characterized but its role in the dentate gyrus has not been well studied.Given the extensive expression of HCAR1 in the dentate gyrus, we wish to understand its action in the DG. Dentate granule cells are thought to act as a gate that filters excitation through the hippocampus. Disruption of this gate is implicated in seizure propagation, particularly in temporal lobe epilepsy. We propose to test the hypothesis that lactate activation of HCAR1 contributes to dentate gyrus gating function. Further investigation will position lactate as a novel neuromodulator and a potential target for modulating excitability in epilepsy.

To test this hypothesis, we used a genetically encoded calcium indicator (GCaMP7) to assess excitability in DGCs from C57Bl/6 mice. Mice were stereotaxically injected with a viral mediated mix of GCaMP7 and CaMKII-Cre transgenes to the dorsal and ventral dentate gyrus (DG). Acute hippocampal slices were prepared and calcium fluorescence GCaMP7 expressing DGCs were measured via epifluorescence microscopy. To excite neural networks, potassium concentration in the aCSF was increased from 2 mM (baseline aCSF) to 5 mM (high K+ aCSF). To study the effect of HCAR1 activation, GCaMP7-expressing DG granule cells were perfused with high K+ aCSF containing 10 mM L-lactate or high K+ aCSF containing 100 μM 3-chloro-5-hydroxybenzoic acid(3CL-HBA). 

Preliminary data indicates that lactate increases DGC excitability, contrasting with its inhibitory effects in CA1. In a subset of neurons, we observed rebound excitation during washout, characterized by a transient surge in activity. A similar rebound effect was seen in slices perfused with 3 CL-HBA, HCAR1’s agonist.This suggests that lactate-HCAR1 signaling may not only enhance baseline excitability but also prime DGCs for activity-dependent rebound responses.  

These findings identify the DG as a site of lactate-HCAR1 action. Ongoing and future studies using HCAR1 knockout mice will clarify whether these effects are HCAR1-dependent and their role in seizure susceptibility.