Modulation of striatal neuron activity by cyclic nucleotide signalling and phosphodiesterase inhibition

Abstract

The cyclic nucleotides cAMP and cGMP are common signaling molecules synthesized in neurons following the activation of adenylyl or guanylyl cyclase. In the striatum, the synthesis and degradation of cAMP and cGMP is highly regulated as these second messengers have potent effects on the activity of striatonigral and striatopallidal neurons. This review will summarize the literature on cyclic nucleotide signaling in the striatum with a particular focus on the impact of cAMP and cGMP on the membrane excitability of striatal medium-sized spiny output neurons (MSNs). The effects of non-selective and selective phosphodiesterase (PDE) inhibitors on membrane activity and synaptic plasticity of MSNs will also be reviewed. Lastly, this review will discuss the implications of the effects PDE modulation on electrophysiological activity of striatal MSNs as it relates to the treatment of neurological disorders such as Huntington’s and Parkinson’s disease.

Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning: Clinical Implications

“…Nitric oxide diffuses from these interneurons into dendrites of MSNs that contain high levels of guanylate cyclase, which, when activated, lead to the synthesis of cGMP (Figure 1). In the intact striatum, transient elevations in intracellular cGMP primarily act to increase neuronal excitability and to facilitate glutamatergic fronto-striatal transmission (West and Tseng, 2011; Threlfell and West, 2013). Although the main focus in the fronto-striatal system has been on cAMP signaling, several PDE-Is (also) target cGMP (e.g., PDE1-Is and PDE10-Is) and may exert their effects (additionally) on the cGMP signaling cascade (Padovan-Neto et al, 2015).…”

Therapy development in Huntington disease: From current strategies to emerging opportunities

“…Phosphodiesterase (PDE) 10A is almost exclusively expressed in the striatum, and its activity is linked to the synaptic function of the striatal MSNs whose death is a prominent feature of HD [Coskran and others 2006]. PDE10A regulates cAMP, synaptic plasticity, and response to cortical stimulation [Threlfell and others 2009; Threlfell and West 2013]. PDE10A expression in early pre-manifest HD is decreased in striatum and pallidum, and increased in motor thalamic nuclei, compared to matched healthy controls.…”

Application of neurophysiological biomarkers for Huntington's disease: Evaluating a phosphodiesterase 9A inhibitor

“…Most importantly, one of the critical goals of our studies was to establish if auditory gating deficit in these transgenic animals could serve as a translational biomarker in drug development of Huntington's disease. Phosphodiesterase (PDE) inhibitors have been considered as potential treatments for Huntington's disease (Azevedo et al, 2014;Mrzljak and Munoz-Sanjuan, 2013;Threlfell and West, 2013) since previous findings have indicated dysregulations of PDEs activities, leading to a decrease in cyclic guanosine monophosphate (cGMP) levels in the striatum and hippocampus in Huntington's disease patients and Huntington's disease transgenic animals (Hebb et al, 2004;Saavedra et al, 2013). Therefore, effects of PF-04447943 (Fig.…”