Role of Phosphodiesterase 4D in Memory and Cognition

Inhibition of PDE4 has been proposed as a potential treatment for series of neuropsychological conditions including memory deficits. However, most centrally acting PDE4 inhibitors have accompanying tolerability issues such as emesis and diarrhea. Therefore, it is critical to elucidate the role of each subtype of PDE4 (namely PDE4A, B and D in the brain), so that unwanted adverse effects may be avoided. Using a selective PDE4D inhibitor, BPN14770, our data suggested that PDE4D might play a critical role in mediating behaviors related to memory and cognition. BPN14770 achieves its highly selective inhibition of PDE4D through allosteric binding to the phenylalanine, which is only present in the primates, in the UCR2 region of the enzyme. As a result, the compound inhibits human and mouse PDE4D with IC50s of 8 and 130 nM, respectively. In order to elucidate the involvement of PDE4D in the memory process in intact animals, we generated a “humanized” mouse line (PEDD) by mutating the mouse UCR2 tyrosine271 to phenylalanine. In the in vitro competition binding assay with 3 H labeled rolipram, BPN14770 exhibited a preferred 2‐site binding mode with the PEDD but not the wild‐type mouse brain homogenate, suggesting that the compound may be able to bind with PDE4D with different affinities in the wild‐type and PEDD mouse brains. It was then demonstrated that in both the wild‐type and PEDD mice, BPN14770 were able to improve cognition, with the minimum effective doses of 1 and 0.01 mg/kg in the novel object recognition (NOR) test, respectively. However, such dose‐response shift was not present with rolipram, a non‐selective PDE4 inhibitor. These behavioral changes were supported by elevated brain cAMP levels in the mouse brain 1 hour after treatment, which showed a similar dose‐response shift between the wild‐type and PEDD mice. Moreover, BPN‐14770 enhanced the long‐term potential in hippocampal slices obtained from both the wild‐type and PEDD mice, with the minimum effective concentration of the latter being 10‐fold smaller. Neurochemical analyses of brain lysates from PEDD mice suggested that such behavioral changes may be due to altered synaptic function, especially in the post synapses, in the prefrontal cortex and hippocampus, as indicated by increased phosphorylation of synapsin and PSD95, as well as molecular targets downstream of cAMP, such as phosphorylation of CREB and BDNF. Taken together, our data suggested that PDE4D plays an indespensable role in regulation of memory and cognition. Support or Funding Information This work was supported by research grants from National Institute of Mental Health to Dr. M. E Gurney (No. R44MH091791).