Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington’s Disease Models

Abstract

Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT.

Striatal molecular alterations in HD gene carriers: a systematic review and meta-analysis of PET studies

“…Mutant HTT (mHTT) decreases PDE10A mRNA expression levels in the striatum,63 66 and inhibition of PDE10A reduces the loss of striatal and cortical neurons and delays the development of neurological deficits in HD animal models 64 65. A recent preclinical study has shown that chronic PDE10 inhibition starting at presymptomatic ages decreases the onset of mHTT-induced corticostriatal transmission deficits and improves cortically driven indirect pathway activity in HD animal models 67. Our results confirm the relevance of this enzyme in HD pathology and suggest that PDE10A could be a potential novel biomarker of striatal MSNs integrity.…”

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease

“…The enhancement of striatopallidal synaptic strength increased the ability of a volley in iSPN axons to pause ongoing GPe neuronal activity in the Q175 het model. Thus, boosting the strength of striatopallidal synapses on prototypical GPe neurons could compensate for an impairment in corticostriatal excitation of iSPNs . The deficit in dendritic integration and excitability of HD iSPNs inferred from these studies has recently been challenged by Sebastianutto and colleagues .…”

“…This deficit is paralleled by a reduction in dendritic excitability of iSPNs (unpublished observations). As axospinous cortical synapses constitute the principal source of excitatory drive to normally quiescent iSPNs, these changes suggest that the indirect pathway becomes hypoexcitable in the early stages of HD …”

Unravelling and Exploiting Astrocyte Dysfunction in Huntington’s Disease

“…HD MSNs show a progressive phenotype of emerging intrinsic hyperexcitability, whereby cells become modestly depolarized, exhibit reduced rheobase in response to current injection, and exhibit significantly higher membrane resistance around resting states, implying the loss of hyperpolarizing conductances that maintain quiescence. These findings are progressive and have been demonstrated in both R6/2 mice as early as 5–7 weeks [54–58] and in Q175 KI mice around 4 months of age [59–61]. It is likely that a loss of intrinsic MSN potassium conductances at least in part underlies this phenomenon; loss of inwardly rectifying potassium channels (Kirs) are likely contributors [56, 62] as they are largely responsible for maintaining Vm, and respective gene expression is known to be decreased [56, 62].…”