Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 7; pp. E1618 - E1626
• Main Authors: Dargaei, Zahra, Bang, Jee Yoon, Mahadevan, Vivek, Khademullah, C. Sahara, Bedard, Simon, Parfitt, Gustavo Morrone, Kim, Jun Chul, Woodin, Melanie A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13-02-2018
• Series: PNAS Plus
• Subjects: Aberration; Animal cognition; Animal memory; Animals; Biological Sciences; Bumetanide; Bumetanide - administration & dosage; Chloride transport; Chlorides; Cognitive ability; Disease Models, Animal; Extrusion; Female; gamma-Aminobutyric Acid - metabolism; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - psychology; Huntington's disease; Huntingtons disease; Inhibition; K Cl- Cotransporters; Learning; Male; Memory; Memory - drug effects; Memory Disorders - etiology; Memory Disorders - metabolism; Memory Disorders - psychology; Mice; Mice, Transgenic; PNAS Plus; Potassium-chloride cotransporter; Proteins; Rodents; Solute Carrier Family 12, Member 2 - genetics; Solute Carrier Family 12, Member 2 - metabolism; Symporters - genetics; Symporters - metabolism; γ-Aminobutyric acid; GABA; chloride; Huntington’s disease; learning; synaptic inhibition
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1716871115

Huntington’s disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice. The reduced expression of the Cl⁻-extruding cotransporter KCC2 is accompanied by an increase in the Cl⁻-importing cotransporter NKCC1, which together result in excitatory GABA in the hippocampi of HD mice. NKCC1 inhibition by the FDA-approved NKCC1 inhibitor bumetanide abolished the excitatory action of GABA and rescued the performance of R6/2 mice on hippocampal-associated behavioral tests.