The phosphodiesterase PDE4D, that also receives substantial support, is an enzyme expessed in neurons and other cells in brain in a number of regions that include hippocampus. PDE4D knockouts display altered results in “antidepressant” testing [272]. Variants at the PDE4D locus have been associated with a number of additional human phenotypes. PDE4D SNPs have been associated with neuroticism in the initial analyses of data from Sample 19 [9]. A number of studies, but not all, have linked and/or associated PDE4D haplotypes with altered risk of stroke [273]. A PDE4D SNP has been associated with sleepiness in Framingham study subjects in 100,000 SNP genome wide association [274]. Rolipam and other PDE4D inhibitors or stimulators have been extensively characterized, providing starting points for more synthesis of more selective drugs [275]. Memory-enhancing effects of PDE4 inibitors documented in rodent behavioral assays, and provide relatively straightforward links with the genome wide association data that we review here [12].
