Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: Evidence for altered striatal function

Abstract

PDE10A is a newly identified phosphodiesterase that is highly expressed by the medium spiny projection neurons of the striatum. In order to investigate the physiological role of PDE10A in the central nervous system, PDE10A knockout mice (PDE10A^−/−) were characterized both behaviorally and neurochemically. PDE10A^−/− mice showed decreased exploratory activity and a significant delay in the acquisition of conditioned avoidance behavior when compared to wild-type (PDE10A^+/+) mice. However, in a variety of other well-characterized behavioral tasks, including the elevated plus maze (anxiety), forced swim test (depression), hot plate (nociception) and two memory models (passive avoidance and Morris water maze), PDE10A^−/− mice performed similarly to wild-type mice. When challenged with PCP or MK-801, PDE10A^−/− mice showed a blunted locomotor response in comparison to PDE10A^+/+ mice. In contrast, PDE10A^−/− and PDE10A^+/+ mice responded similarly to the locomotor stimulating effects of amphetamine and methamphetamine. Our findings suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation. These results are discussed in relationship to the hypothesis that PDE10A inhibition presents a novel treatment for psychosis.

Introduction

The cyclic nucleotides cAMP and cGMP are second messengers mediating intracellular signal transduction across the phylogenetic spectrum. A key element in regulation of these signaling pathways is metabolic inactivation of cyclic nucleotides by cyclic nucleotide phosphodiesterases (PDEs) (for review, Soderling and Beavo, 2000). In mammals, PDEs comprise a superfamily of enzymes divided into 11 families that are differentially localized throughout the organism. The ability to selectively regulate cyclic nucleotide signaling through pharmacological manipulation of these enzymes offers unique therapeutic opportunities.

The newly described PDE10A is particularly interesting in this regard due to its relatively specific expression in the brain. PDE10A was first identified by homology screening of EST databases and homologues of the mouse, rat and human enzymes have been characterized (Fujishige et al., 1999, Loughney et al., 1999, Soderling et al., 1999). PDE10A is an 89 kDA protein capable of hydrolyzing both cAMP and cGMP. Initial northern and dot blot studies demonstrated PDE10A expression within the brain and in particular, the striatum (Fujishige et al., 1999, Loughney et al., 1999, Soderling et al., 1999). Subsequent localization studies using in situ hybridization and immunohistochemistry indicate PDE10A mRNA and protein are highly expressed in the medium spiny projection neurons of the striatum (Seeger et al., 2003). High levels of PDE10A protein are found in the cell bodies and dendritic fields of these neurons as well as in the regions to which these neurons project.

The medium spiny neurons of the striatum function as the principal input site to the basal ganglia (Wilson, 1998). The basal ganglia are a series of interconnected subcortical nuclei that integrate widespread cortical input with dopaminergic signaling to plan, facilitate, and execute relevant motor and cognitive patterns while suppressing unwanted or irrelevant patterns (for review, see Graybiel, 2000). Striatal dysfunction is implicated in a number of CNS disorders including Parkinson's disease, Huntington's disease, schizophrenia and obsessive-compulsive disorders. There is considerable evidence that the cAMP (Girault and Greengard, 2004) and cGMP (West and Grace, 2004) signaling pathways play significant roles in the regulation of medium spiny neuron excitability. Thus, the pattern of localization of PDE10A within these neurons suggests that changes in the activity of this enzyme may affect striatal function and PDE10A inhibitors may provide therapeutic benefit in the treatment of diseases associated with this brain region.

Until recently, speculation around the functional role of PDE10A in the central nervous system has been based solely on its localization within the brain. We have now produced a mouse in which the gene for PDE10A is constitutively disrupted and in the present studies use these mice to explore the physiological function of PDE10A. Specifically, PDE10A knockout (PDE10A^−/−) mice were characterized across a broad spectrum of well-established behavioral tests including an assessment of behavioral responsiveness to dopamine releasing agents and NMDA receptor antagonists. The results suggest that PDE10A normally functions to inhibit striatal output by reducing medium spiny neuron excitability.