Phosphodiesterase 9A Inhibition Facilitates Corticostriatal Transmission in Wild-Type and Transgenic Rats That Model Huntington's Disease.

Shreaya Chakroborty,Grace E. Stutzmann,Vahri Beaumont,Alexander M. Dec,Anthony R. West,Peter W. Campbell,Fredric P. Manfredsson

doi:10.3389/fnins.2020.00466

Abstract

Huntington’s disease (HD) results from abnormal expansion in CAG trinucleotide repeats within the HD gene, a mutation which leads to degeneration of striatal medium-sized spiny neurons (MSNs), deficits in corticostriatal transmission, and loss of motor control. Recent studies also indicate that metabolism of cyclic nucleotides by phosphodiesterases (PDEs) is dysregulated in striatal networks in a manner linked to deficits in corticostriatal transmission. The current study assessed cortically-evoked firing in electrophysiologically-identified MSNs and fast-spiking interneurons (FSIs) in aged (9–11 months old) wild-type (WT) and BACHD transgenic rats (TG5) treated with vehicle or the selective PDE9A inhibitor PF-04447943. WT and TG5 rats were anesthetized with urethane and single-unit activity was isolated during low frequency electrical stimulation of the ipsilateral motor cortex. Compared to WT controls, MSNs recorded in TG5 animals exhibited decreased spike probability during cortical stimulation delivered at low to moderate stimulation intensities. Moreover, large increases in onset latency of cortically-evoked spikes and decreases in spike probability were observed in FSIs recorded in TG5 animals. Acute systemic administration of the PDE9A inhibitor PF-04447943 significantly decreased the onset latency of cortically-evoked spikes in MSNs recorded in WT and TG5 rats. PDE9A inhibition also increased the proportion of MSNs responding to cortical stimulation and reversed deficits in spike probability observed in TG5 rats. As PDE9A is a cGMP specific enzyme, drugs such as PF-04447943 which act to facilitate striatal cGMP signaling and glutamatergic corticostriatal transmission could be useful therapeutic agents for restoring striatal function and alleviating motor and cognitive symptoms associated with HD.

Highlights

Huntington’s disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by a polyglutamine (CAG) expansion within the gene encoding for the huntingtin protein (HDCRG, 1993)
Several studies using in vivo recording methods have demonstrated that monosynaptic spike activity in striatal medium-sized spiny neurons (MSNs) and fast-spiking interneurons (FSIs) is reliably driven by corticostriatal inputs, and that specific characteristics exhibited by these evoked responses can be utilized to differentiate between these neuronal subtypes (Mallet et al, 2005, 2006; Sharott et al, 2009, 2012; Padovan-Neto et al, 2015)
Durations that are always >1 ms, whereas FSIs exhibit much shorter duration Action potential (AP) averaging

Summary

Introduction

Huntington’s disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by a polyglutamine (CAG) expansion within the gene encoding for the huntingtin protein (HDCRG, 1993). Neuropathological studies point to preferential degeneration of striatopallidal medium-sized spiny neurons (MSNs) and dysfunction of corticostriatal projection neurons (Wong et al, 1982; Reiner et al, 1988; Vonsattel et al, 2008). Electrophysiological studies of transgenic rodent models of HD have demonstrated a profound impairment in corticostriatal transmission characterized by imbalances in glutamate and GABA transmission, disruptions in striatal network activity, and abnormal uncoordinated MSN firing activity (Cepeda et al, 2007; Miller et al, 2010; Andre et al, 2011; Heikkinen et al, 2012; Indersmitten et al, 2015; Bunner and Rebec, 2016; Raymond, 2017)

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Discussion

Conclusion