Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue

Abstract

Lactate can be used by neurons as an energy substrate to support their activity. Evidence suggests that lactate also acts on a metabotropic receptor called HCAR1, first described in the adipose tissue. Whether HCAR1 also modulates neuronal circuits remains unclear. In this study, using qRT-PCR, we show that HCAR1 is present in the human brain of epileptic patients who underwent resective surgery. In brain slices from these patients, pharmacological HCAR1 activation using a non-metabolized agonist decreased the frequency of both spontaneous neuronal Ca2+ spiking and excitatory post-synaptic currents (sEPSCs). In mouse brains, we found HCAR1 expression in different regions using a fluorescent reporter mouse line and in situ hybridization. In the dentate gyrus, HCAR1 is mainly present in mossy cells, key players in the hippocampal excitatory circuitry and known to be involved in temporal lobe epilepsy. By using whole-cell patch clamp recordings in mouse and rat slices, we found that HCAR1 activation causes a decrease in excitability, sEPSCs, and miniature EPSCs frequency of granule cells, the main output of mossy cells. Overall, we propose that lactate can be considered a neuromodulator decreasing synaptic activity in human and rodent brains, which makes HCAR1 an attractive target for the treatment of epilepsy.

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes

“…Lactate has traversed a long way from being initially viewed as little more than mere cellular waste, to become a relevant metabolite for brain physiology 22,42 . Astrocytederived lactate has been shown to modulate neuronal functions via multiple mechanisms [59][60][61][62][63][64][65][66][67] . Most of these proposed mechanisms, however, are linked to the role of lactate as an energy substrate for neuronal activity.…”

Lactate Neuroprotection against Transient Ischemic Brain Injury in Mice Appears Independent of HCAR1 Activation

“…Nevertheless, at present, how lactate exerts neuroprotection remains an open question. The discovery of HCAR1 [ 11 , 12 ], present in the brain [ 4 , 13 , 14 , 16 , 17 ], prompted the idea of a possible dual-protective effect of lactate in the context of stroke; a metabolic effect and a signaling effect mediated (possibly) by HCAR1 [ 4 ]. Lactate’s metabolic role in post-ischemic neuroprotection stands on several pieces of evidence.…”

“…Finally, as these are in vivo experiments that affect the whole animal, we cannot discard systemic effects related to the HCAR1 KO, as the lactate activation of HCAR1 inhibits lipolysis in adipose tissue [ 12 ] and has been related to blood pressure control [ 33 ]. Neither can we discard the possibility that systemic effects could be behind the apparent discrepancy between the responses to HCAR1 agonists observed in in vitro, ex vivo and in vivo experimental systems [ 4 , 14 ].…”

“…However, the mechanisms by which the administration of exogenous lactate provides protection are yet to be unraveled. Since the discovery that lactate can act as an agonist of the hydroxycarboxylic acid receptor 1 (HCAR1) [ 11 , 12 ], expressed in rodent and human brain tissue [ 13 , 14 , 15 , 16 , 17 ], a dual mechanism of action for neuroprotection has been proposed [ 4 ]. On the one hand, lactate could be used as a preferential metabolic substrate providing energy to suffering neurons [ 18 , 19 , 20 ].…”

Nutritional and metabolic signalling through GPCRs

“…As the brain is a well-known lactate-rich environment, lactate sensing via membrane receptor has emerged in both physiological and pathological conditions. Neurons sensing lactate can activate GPR81 resulting in a decrease in their excitability [71]. Also, ischaemia or intense physical exercise leads to the hypoperfusion of the brain, and lactate acts as a neuroprotective agent.…”