| First Author | Serranilla M | Year | 2024 |
| Journal | J Neurosci | Volume | 44 |
| Issue | 50 | PubMed ID | 39500579 |
| Mgi Jnum | J:360375 | Mgi Id | MGI:7790425 |
| Doi | 10.1523/JNEUROSCI.0215-24.2024 | Citation | Serranilla M, et al. (2024) Restoring Compromised Cl(-) in D2 Neurons of a Huntington's Disease Mouse Model Rescues Motor Disability. J Neurosci 44(50) |
| abstractText | Huntington's disease (HD) is a progressive neurodegenerative disorder with no cure, characterized by significant neurodegeneration of striatal GABAergic medium spiny neurons (MSNs). Early stages of the disease are characterized by the loss of dopamine 2 receptor-expressing MSNs (D2 MSNs) followed by degeneration of dopamine 1 receptor-expressing MSNs (D1 MSNs), leading to aberrant basal ganglia signaling. While the early degeneration of D2 MSNs and impaired GABAergic transmission are well-documented, potassium chloride cotransporter 2 (KCC2), a key regulator of intracellular chloride (Cl(-)), and therefore GABAergic signaling, has not been characterized in D1 and D2 MSNs in HD. We aimed to investigate whether Cl(-) regulation was differentially altered in D1 and D2 MSNs and may contribute to the early degeneration of D2 MSNs in male and female symptomatic R6/2 mice. We used electrophysiology to record the reversal potential for GABA(A) receptors (E (GABA)), a read-out for the efficacy of Cl(-) regulation, in striatal D1 and D2 MSNs and their corresponding output structures. During the early symptomatic phase (P55-P65), Cl(-) impairments were observed in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl(-) regulation was also dysfunctional in the globus pallidus externa, resulting in GABA-mediated excitation. When we overexpressed KCC2 in D2 MSNs using AAV-mediated delivery, we delayed the onset of motor impairments in R6/2 mice. We demonstrate that Cl(-) homeostasis is differentially altered in D1 and D2 MSNs and may contribute to the enhanced susceptibility of D2 MSNs during HD progression. |
