Complete but not partial inhibition of glutamate transporters exacerbates cortical excitability in the R6/2 mouse model of Huntington’s disease

Abstract

Aim: Deficient glutamate reuptake occurs in the cerebral cortex of Huntington’s disease (HD) patients and murine models. Here we examine the effects of partial or complete blockade of glutamate transporters on excitatory postsynaptic currents (EPSCs) of cortical pyramidal neurons (CPNs). Methods: Whole-cell patch clamp recordings of CPNs in slices from symptomatic R6/2 mice and wildtype (WT) littermates were used to examine the effects of selective or concurrent inhibition of glutamate reuptake transporters. Results: Selective inhibition of the glial glutamate transporter 1 (GLT-1) or the glutamate aspartate transporter (GLAST) produced slight decreases in decay time of evoked EPSCs in CPNs from WT and R6/2 mice with no significant differences between genotypes. In contrast, concurrent inhibition of both transporters with DL-TBOA induced a significant increase in area and decay time and this effect was significantly greater in R6/2 CPNs. Furthermore, full blockade also reduced spontaneous EPSC frequency and exacerbated epileptiform activity in CPNs from symptomatic R6/2 mice. Conclusions: R6/2 CPNs are more sensitive to glutamate accumulation during full inhibition of both glutamate transporters and these neurons have homeostatic mechanisms to cope with inhibition of GLT-1 or GLAST by a mechanism that involves upregulation of either transporter when the other is deficient.

Neuroprotection Role of Vitamin C by Upregulating Glutamate Transporter-1 in Auditory Cortex of Noise-Induced Tinnitus Animal Model

“…The utilization of DL-TBOA enabled us to block the uptake activity of glutamate transporters in the brain. This allows us to gain a clearer understanding of the interactions between Vc and glutamate transporters. − …”

Revealing the contribution of astrocytes to glutamatergic neuronal transmission

“…However, later studies suggested that astrocytes can directly or indirectly modulate synaptic neuronal activity ( Figure 2 ; Nedergaard, 1994 ; Beppu et al, 2021 ) and influence behavior (Lyon and Allen, 2022 ). The first level of regulation is glutamate uptake by astrocytic transporters as they regulate the neurotransmitter levels in the synaptic cleft; these transporters indirectly modulate neuronal transmission (Jabaudon et al, 1999 ), neuronal activity (Estrada-Sánchez et al, 2019 ) and survival (Estrada-Sánchez et al, 2007 , 2019 ). Glutamate uptake can also regulate the availability of glutamine to synthesize glutamate.…”

“…In the R6/2 Huntington’s disease transgenic mouse model, decreased content of GLT-1 and GLAST correlates with increased vulnerability to glutamate-induced toxicity (Estrada-Sánchez et al, 2009 , 2010 ). Likewise, cortical pyramidal neurons in the R6/2 mice are more vulnerable to glutamate-mediated paroxysmal activity during the inhibition of both GLT-1 and GLAST transporters (Estrada-Sánchez et al, 2019 ).…”

Altered Cholesterol Homeostasis in Huntington’s Disease

“…However, the GLT1 ablation does not worsen motor deficits and weight loss in R6/2 mice ( Petr et al, 2013 ). Protein levels of the glutamate transporter GLAST are also decreased in the striatum and cortex of R6/2 mice ( Estrada-Sánchez et al, 2009 ), associated with neuronal vulnerability, and the selective inhibition of both GLT1 and GLAST in R6/2 brain slice worsen electrophysiological properties of HD cortical neurons ( Estrada-Sánchez et al, 2019 ). The astrocytic Kir4.1 channel has a role in the influx of potassium and therefore it is essential to support MSNs electrophysiological properties ( Nwaobi et al, 2016 ).…”