Current Understanding of PDE10A in the Modulation of Basal Ganglia Circuitry

Abstract

The basal ganglia are a forebrain network of interconnected nuclei that are involved in action selection, reward circuits and coordinating movement. PDE10A inhibition has been proposed as a novel way to modulate basal ganglia circuitry and to ameliorate symptoms in Huntington's disease, Parkinson's disease and Schizophrenia. However, despite encouraging results from pre-clinical models, PDE10A inhibitors failed to show efficacy as an antipsychotic in several clinical trials. PDE10A is expressed in the medium spiny neurons of the striatum and works to limit cyclic nucleotide signaling in response to modulatory neurotransmitters like dopamine. In this chapter, we will review the current literature on PDE10A and discuss how inhibition of PDE10A will result in alterations of the basal ganglia circuitry at the biochemical, physiological and behavioral level.

Pivotal role of PDE10A in the integration of dopamine signals in mice striatal D1 and D2 medium-sized spiny neurones

“…This D2/D1 imbalance was consistent with PDE10A inhibitors mimicking the D2 antagonistic action of antipsychotic agents. PDE10A inhibition has therefore been largely studied as a therapeutic strategy in the treatment of schizophrenia or Huntington's disease (Kehler & Nielsen, 2011;Kehler, Ritzén, & Greve, 2007;Menniti et al, 2007;Chappie et al, 2009;Harada et al, 2020;Schülke & Brandon, 2017). Clinical results however did not confirm these expectations.…”

Pivotal role of phosphodiesterase 10A in the integration of dopamine signals in mice striatal D1 and D2 medium‐sized spiny neurones

“…This D 2 /D 1 imbalance was consistent with PDE10A inhibitors mimicking the D 2 antagonistic action of antipsychotic agents. PDE10A inhibition has therefore been largely studied as a therapeutic strategy for the treatment of schizophrenia or Huntington's disease (Chappie et al, 2009;Harada et al, 2020;Kehler et al, 2007;Kehler & Nielsen, 2011;Menniti et al, 2007Menniti et al, , 2020Schülke & Brandon, 2017). While clinical results did not confirm these expectations, a better understanding of PDE10A involvement in dopamine action may eventually reveal the cellular underpinnings of schizophrenia (Menniti et al, 2020).…”

The Emerging Role of Phosphodiesterases in Movement Disorders

“…5 Reduced cAMP levels and CREB activity have been demonstrated in both the cortex and striatum of the HD mouse model, 23 which could be possibly owing to increased cyclic nucleotide degradation by PDEs. 24 The most implicated PDE in HD is PDE10A given that it is particularly enriched in the striatum, 21,25 but there is also suggestion that PDE4A, PDE1B, PDE5, PDE9A, and PDE3 might be playing a FIG. 1.…”

“… 5 Reduced cAMP levels and CREB activity have been demonstrated in both the cortex and striatum of the HD mouse model, 23 which could be possibly owing to increased cyclic nucleotide degradation by PDEs. 24 The most implicated PDE in HD is PDE10A given that it is particularly enriched in the striatum, 21 , 25 but there is also suggestion that PDE4A, PDE1B, PDE5, PDE9A, and PDE3 might be playing a role in HD pathogenesis. 26 , 27 , 28 Tables 1 and 2 summarize the evidence from preclinical and clinical studies, respectively, specifically investigating PDE activity and cyclic nucleotides signaling in HD.…”