Chronic Suppression of Phosphodiesterase 10A Alters Striatal Expression of Genes Responsible for Neurotransmitter Synthesis, Neurotransmission, and Signaling Pathways Implicated in Huntington's Disease

Inhibition of phosphodiesterase 10A (PDE10A) promotes cyclic nucleotide signaling, increases striatal activation and decreases behavioral activity. Enhanced cyclic nucleotide signaling is a well-establish route to producing changes in gene expression. We hypothesized that chronic suppression of PDE10A activity would have significant effects on gene expression in the striatum. A comparison of the expression profile of PDE10A knockout mice (KO) and wild-type (WT) mice following chronic PDE10A inhibition revealed altered expression of 19 overlapping genes with few significant changes outside the striatum or following administration of a PDE10A inhibitor to KO animals. Chronic inhibition of PDE10A produced up-regulation of mRNAs encoding genes that included prodynorphin, synaptotagmin10, phosphodiesterase 1C (PDE1C), glutamate decarboxylase 1 (GAD67), diacylglycerol O-acyltransferase (DGAT2) and a down regulation of mRNA encoding choline acetyltransferase (ChAT) and Kv1.6, suggesting long-term suppression of the PDE10A enzyme is consistent with altered striatal excitability and potential utility as a antipsychotic therapy. Additionally, upregulation of mRNA encoding histone H3 and downregulation of histone deacetylase 4, follistatin and claspin mRNAs suggests activation of molecular cascades capable of neuroprotection. We utilized lentiviral delivery of CRE-luciferase reporter constructs into the striatum and live animal imaging of TP-10 induced luciferase activity to further demonstrate PDE10 inhibition results in CRE-mediated transcription. Consistent with potential neuroprotective cascades, we also demonstrate phosphorylation of mitogen- and stress-activated kinases 1 (MSK1) and histone H3 in vivo following TP-10 treatment. The observed changes in signaling and gene expression are predicted to provide neuroprotective effects in models of Huntington9s Disease.