Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase

• Published in: Neuroscience 2006-01, Vol.139 (2), p.597-607
• Main Authors: Xie, Z., Adamowicz, W.O., Eldred, W.D., Jakowski, A.B., Kleiman, R.J., Morton, D.G., Stephenson, D.T., Strick, C.A., Williams, R.D., Menniti, F.S.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blotting, Western - methods; Calbindin 2; Choline O-Acetyltransferase - metabolism; CNS; Corpus Striatum - cytology; Corpus Striatum - enzymology; Cynomolgus; Fundamental and applied biological sciences. Psychology; immunohistochemistry; Male; medium spiny neurons; Microscopy, Immunoelectron - methods; Neurons - enzymology; Neurons - ultrastructure; Nitric Oxide Synthase Type I - metabolism; Parvalbumins - metabolism; phosphodiesterase; Phosphoric Diester Hydrolases - metabolism; Rats; Rats, Sprague-Dawley; S100 Calcium Binding Protein G - metabolism; striatum; Subcellular Fractions - enzymology; Subcellular Fractions - ultrastructure; Synaptosomes - enzymology; Synaptosomes - ultrastructure; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2005.12.042

PDE10A is a recently identified phosphodiesterase that is highly expressed by the GABAergic medium spiny projection neurons of the mammalian striatum. Inhibition of PDE10A results in striatal activation and behavioral suppression, suggesting that PDE10A inhibitors represent a novel class of antipsychotic agents. In the present studies we further elucidate the localization of this enzyme in striatum of rat and cynomolgus monkey. We find by confocal microscopy that PDE10A-like immunoreactivity is excluded from each class of striatal interneuron. Thus, the enzyme is restricted to the medium spiny neurons. Subcellular fractionation indicates that PDE10A is primarily membrane bound. The protein is present in the synaptosomal fraction but is separated from the postsynaptic density upon solubilization with 0.4% Triton X-100. Immuno-electron microscopy of striatum confirms that PDE10A is most often associated with membranes in dendrites and spines. Immuno-gold particles are observed on the edge of the postsynaptic density but not within this structure. Our studies indicate that PDE10A is associated with post-synaptic membranes of the medium spiny neurons, suggesting that the specialized compartmentation of PDE10A enables the regulation of intracellular signaling from glutamatergic and dopaminergic inputs to these neurons.