Modulation of hippocampal excitability via the hydroxycarboxylic acid receptor 1

Abstract

In addition to its prominent role as an energetic substrate in the brain, lactate is emerging as a signaling molecule capable of controlling neuronal excitability. The finding that the lactate-activated receptor (hydroxycarboxylic acid receptor 1; HCA1) is widely expressed in the brain opened up the possibility that lactate exerts modulation of neuronal activity via a transmembranal receptor-linked mechanism. Here, we show that lactate causes biphasic modulation of the intrinsic excitability of CA1 pyramidal cells. In the low millimolar range, lactate or the HCA1 agonist 3,5-DHBA reduced the input resistance and membrane time constant. In addition, activation of HCA1 significantly blocked the fast inactivating sodium current and increased the delay from inactivation to a conducting state of the sodium channel. As the observed actions occurred in the presence of 4-CIN, a blocker of the neuronal monocarboxylate transporter, the possibility that lactate acted via neuronal metabolism is unlikely. Consistently, modulation of the intrinsic excitability was abolished when CA1 pyramidal cells were dialyzed with pertussis toxin, indicating the dependency of a G -protein-coupled receptor. The activation of HCA1 appears to serve as a restraining mechanism during enhanced network activity and may function as a negative feedback for the astrocytic production of lactate.

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

“…the action potential amplitude, threshold, and half-width in subsequent action potentials (Table 2), unlike shown earlier with 5 mmol/L lactate in CA1 neurons. 44 It has been shown that resting and active properties of subicular neurons are different from CA1 neurons. 20 The lack of effect with 6 mmol/L lactate in the subicular neurons may be ascribed to subtle differences in the voltage-gated sodium channel properties between these two cell types that have different action potential characteristics and propensities to burst.…”

Extracellular levels of glucose in the hippocampus and striatum during maze training for food or water reward in male rats

“…For example, lactate actions include support for the energetic needs of astrocytes, perhaps thereby sparing glucose consumption by astrocytes in support of glucose use by neurons [102,[106][107][108][109][110]. Lactate also activates GPR81 (or HCAR1) receptors, which can regulate neural excitability [111][112] and possibly modulate neural plasticity and memory [113]. GPR81…”

The roles of GRP81 as a metabolic sensor and inflammatory mediator

“…The contradictory results may be attributed to the dubious specificity of GPR81 antibodies (de Castro Abrantes et al, 2019). Both lactate and 3,5-DHBA inhibited mouse cortical glutamatergic and GABAergic neuronal activity via monitoring decreased calcium transient frequency (Bozzo et al, 2013) by activating GPR81, which will inhibit the AC-cAMP intracellular cascade through coupling with the G iα subunit (Herrera-Lopez & Galvan, 2018). In addition, GPR81 also interacts with G iβɣ subunit, which regulates phospholipase C (PLC) to reduce neuronal excitability (de Castro Abrantes et al, 2019).…”

“…GPR81 has been known to inhibit the level of cAMP in an autocrine loop to reduce lipolysis and preserve energy, so also in the brain (K. H. Lauritzen et al, 2014). GPR81 seems to serve as a restraining mechanism during enhanced network activity and disposes the surplus lactate produced by astrocytic glycolysis (Herrera-Lopez & Galvan, 2018). It inhibits cellular cAMP generation, hence slowing glycolysis rates in response to lactate increase.…”

“…The broad expression of GPR81 across different tissues suggests that GPR81 likely may have multiple physiological functions in our body. Recent studies showed that GPR81 can be a metabolic sensor (Ahmed et al, 2010) to take part in lipid metabolism (Liu et al, 2012), neuronal excitability changes (de Castro Abrantes et al, 2019;Herrera-Lopez & Galvan, 2018), and cellular development and survival (Ohno et al, 2018;Roland et al, 2014;Wu et al, 2018). Another primary function of GPR81 is modulating the inflammatory response (Harun-Or-Rashid & Inman, 2018;Hoque, Farooq, Ghani, Gorelick, & Mehal, 2014).…”