Glucose transporter 3 gene deficiency modifies Huntington's disease progression in zQ175 model mice.

Abstract

In Huntington's disease (HD), reduced neuronal glucose transport plays an important role. We investigated the effects of GLUT3 knock-down (KD) on the trajectory of the HD phenotype in zQ175 model mice. GLUT3 (G3) expression was reduced in heterozygous (HT) and homozygous mice. zQ175 mice when crossed with Emx1-G3KD HT mice, created conditional GLUT3-KD in cortical pyramidal neurons (CPNs), allowing examination of Q175WT/G3WT, Q175WT/G3KD, Q175HT/G3WT, and Q175HT/G3KD genotypes. Immunohistochemically, higher GLUT3 expression and number of GLUT3 positive CPNs were observed in Q175WT/G3WT compared to Q175WT/G3KD, Q175HT/G3WT, and Q175HT/G3KD, with no difference among these three groups, supporting a protective floor effect. Behaviorally, Q175HT/G3KD mice faced difficulty learning tasks and thereby performed worse than the other three groups. Electrophysiologically, the basic membrane properties of cortical pyramidal neurons (CPNs) were not affected. In contrast, in striatal medium-sized spiny neurons (MSNs) significant increases in cell membrane input resistance occurred in Q175HT/G3WT and Q175HT/G3KD compared to Q175WT/G3WT and Q175WT/G3KD, with no difference between Q175HT/G3WT and Q175HT/G3KD. Upon examination of spontaneous glutamatergic and GABAergic synaptic currents, the cumulative interevent intervals (IEI) revealed increased glutamatergic activity in GLUT3 KD, suggesting increased cortical excitability, with a concomitant compensatory increase in GABA synaptic activity. In striatal MSNs, a subtle but significant decrease in sEPSCs frequency occurred between Q175HT/G3WT and Q175HT/G3KD. The key change was an increase in frequency of sIPSCs in Q175HT/G3WT and Q175HT/G3KD compared to Q175WT/G3WT. These results underscore complex modifications of the HD phenotype among groups related to the interplay between GLUT3 KD, compensatory mechanisms, and floor effects.