Phosphodiesterase 9A Regulates Central cGMP and Modulates Responses to Cholinergic and Monoaminergic Perturbation In Vivo

Abstract

Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a highaffinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.

Targeting the dopamine D1 receptor or its downstream signalling by inhibiting phosphodiesterase‐1 improves cognitive performance

“…This is consistent with data on other PDE inhibitors, as previously reported by us and others (Verhoest et al, 2009; Kroker et al, 2014). Nevertheless, the assay used can demonstrate pharmacological activity of PDE inhibitors (Kleiman et al, 2012; Kroker et al, 2014) such as ITI‐214, in relevant brain areas.…”

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

“…PDE9 has the highest affinity for cGMP next to cAMP, and its inhibitors have shown promising cognition enhancing results in preclinical studies with healthy and pharmacologically impaired rodents [94][95][96]. Two PDE9 inhibitors are approved for clinical testing.…”

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

“…The remaining PDE families are capable of degrading both substrates. PDE9 inhibitors have been studied for their potential applications to treat diabetes (Deninno et al, 2009;Shao et al, 2014) and central nervous system diseases such as Alzheimer's disease (Wunder et al, 2005;van der Staay et al, 2008;Verhoest et al, 2009Verhoest et al, , 2012Hutson et al, 2011;Vardigan et al, 2011;Claffey et al, 2012;Kleiman et al, 2012;Kroker et al, 2012Kroker et al, , 2014Liddie et al, 2012;Schwam et al, 2014;Singh and Patra, 2014;Heckman et al, 2015;Nagy et al, 2015).…”