Regulation of GABA Equilibrium Potential by mGluRs in Rat Hippocampal CA1 Neurons

Abstract

The equilibrium potential for GABA-A receptor mediated currents (EGABA) in neonatal central neurons is set at a relatively depolarized level, which is suggested to be caused by a low expression of K+/Cl- co-transporter (KCC2) but a relatively high expression of Na+-K+-Cl- cotransporter (NKCC1). Theta-burst stimulation (TBS) in stratum radiatum induces a negative shift in EGABA in juvenile hippocampal CA1 pyramidal neurons. In the current study, the effects of TBS on EGABA in neonatal and juvenile hippocampal CA1 neurons and the underlying mechanisms were examined. Metabotropic glutamate receptors (mGluRs) are suggested to modulate KCC2 and NKCC1 levels in cortical neurons. Therefore, the involvement of mGluRs in the regulation of KCC2 or NKCC1 activity, and thus EGABA, following TBS was also investigated. Whole-cell patch recordings were made from Wistar rat hippocampal CA1 pyramidal neurons, in a slice preparation. In neonates, TBS induces a positive shift in EGABA, which was prevented by NKCC1 antisense but not NKCC1 sense mRNA. (RS)-a-Methyl-4-carboxyphenylglycine (MCPG), a group I and II mGluR antagonist, blocked TBS-induced shifts in both juvenile and neonatal hippocampal neurons. While blockade of mGluR1 or mGluR5 alone could interfere with TBS-induced shifts in EGABA in neonates, only a combined blockade could do the same in juveniles. These results indicate that TBS induces a negative shift in EGABA in juvenile hippocampal neurons but a positive shift in neonatal hippocampal neurons via corresponding changes in KCC2 and NKCC1 expressions, respectively. mGluR activation seems to be necessary for both shifts to occur while the specific receptor subtype involved seems to vary.

WNK3 Maintains the GABAergic Inhibitory Tone, Synaptic Excitation and Neuronal Excitability via Regulation of KCC2 Cotransporter in Mature Neurons

“…The value of E GABA , representing the polarizing state of GABAergic signaling, is controlled by both NKCC1 and KCC2 during the development and maturation of neurons (Lu et al, 1999 ; Ben-Ari et al, 2012 ). In cortical and hippocampal neurons, CCCs control the equilibrium potential ( E GABA ) of GABA A R-mediated current and consequently regulate the efficacy of GABAergic inhibition (Yang et al, 2015 ). NKCC1 and KCC2 are two important kinases in GABAergic signaling under both normal and pathophysiological conditions, such as epilepsy (Zhu et al, 2008 ).…”

Pin1 Is Regulated by CaMKII Activation in Glutamate-Induced Retinal Neuronal Regulated Necrosis

“…mGluR1 and mGluR5 are coupled to the stimulation of the phosphatidylinositol hydrolysis/calcium signal transduction, whereas the others are linked to the inhibition of the CAMP cascade (Hayashi et al, 1994). MCPG has been reported to be a non-specific antagonist of group I (mGluR1 and mGluR5) and group II receptors (mGluR2 and mGluR3) (Kohlmeier et al, 2013; Yang et al, 2015), exhibiting little effect on either the NMDA receptor or the AMPA/kainate receptor (Jane et al, 1993). Results in Figure 2 directly demonstrate that iGluRs may be involved in the glutamate-induced rise of calcium.…”

Trkb-IP3 Pathway Mediating Neuroprotection in Rat Hippocampal Neuronal Cell Culture Following Induction of Kainic Acid

“…Moreover, a study using a theta-burst stimulation (TBS)-induced model reported that activation of metabotropic glutamate receptors (mGluRs) is involved in KCC2 in cortical neurons, leading to increased intracellular Ca 2+ ( 61 ). GABA A R may also be affected by the GluR5 kainate receptor after KA treatment.…”