Open AccessComplete but not partial inhibition of glutamate transporters exacerbates cortical excitability in the R6/2 mouse model of Huntington’s disease
Author(s) -
EstradaSánchez Ana María,
Castro Daniel,
PortilloOrtiz Kenia,
Jang Katrina,
NedjatHaiem Michael,
Levine Michael S.,
Cepeda Carlos
Publication year - 2019
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13070
Subject(s) - glutamate receptor , transporter , excitatory postsynaptic potential , neuroscience , blockade , pharmacology , chemistry , excitatory amino acid transporter , reuptake , glutamatergic , biology , biochemistry , inhibitory postsynaptic potential , receptor , gene , serotonin
Summary 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 wild‐type (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.