Loss of Function of Phosphodiesterase 11A4 Shows that Recent and Remote Long-Term Memories Can Be Uncoupled.

Systems consolidation is a process by which memories initially require the hippocampus for recent long-term memory (LTM) but then become increasingly independent of the hippocampus and more dependent on the cortex for remote LTM. Here, we study the role of phosphodiesterase 11A4 (PDE11A4) in systems consolidation. PDE11A4, which degrades cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is preferentially expressed in neurons of CA1, the subiculum, and the adjacently connected amygdalohippocampal region. In male and female mice, deletion of PDE11A enhances remote LTM for social odor recognition and social transmission of food preference (STFP) despite eliminating or silencing recent LTM for those same social events. Measurement of a surrogate marker of neuronal activation (i.e., Arc mRNA) suggests the recent LTM deficits observed in Pde11 knockout mice correspond with decreased activation of ventral CA1 relative to wild-type littermates. In contrast, the enhanced remote LTM observed in Pde11a knockout mice corresponds with increased activation and altered functional connectivity of anterior cingulate cortex, frontal association cortex, parasubiculum, and the superficial layer of medial entorhinal cortex. The apparent increased neural activation observed in prefrontal cortex of Pde11a knockout mice during remote LTM retrieval may be related to an upregulation of the N-methyl-D-aspartate receptor subunits NR1 and NR2A. Viral restoration of PDE11A4 to vCA1 alone is sufficient to rescue both the LTM phenotypes and upregulation of NR1 exhibited by Pde11a knockout mice. Together, our findings suggest remote LTM can be decoupled from recent LTM, which may have relevance for cognitive deficits associated with aging, temporal lobe epilepsy, or transient global amnesia.

Identification of new PDE9A isoforms and how their expression and subcellular compartmentalization in the brain change across the life span.

3',5'-Cyclic nucleotide phosphodiesterases (PDEs) degrade 3',5' cyclic adenonosine monophosphate (cAMP) and 3',5' cyclic guanosine monophosphate (cGMP), with PDE9A having the highest affinity for cGMP. We show PDE9A6 and 3 novel PDE9 isoforms (PDE9X-100, PDE9X-120, and PDE9X-175) are reliably detected in the brain and lung of mice, whereas PDE9A2 and other isoforms are found elsewhere. PDE9A localizes to the membrane in all organs except the bladder, where it is cytosolic. Brain additionally shows PDE9 in the nuclear fraction. PDE9A mRNA expression/localization dramatically changes across neurodevelopment in a manner that is strikingly consistent between mice and humans (i.e., decreased expression in the hippocampus and cortex and inverted-U in the cerebellum). Study of the 4 PDE9 isoforms in the mouse brain from postnatal day 7 through 24 months similarly identifies dramatic effects of age on expression and subcellular compartmentalization that are isoform specific and brain region specific. Finally, PDE9A mRNA is elevated in the aged human hippocampus with dementia when there is a history of traumatic brain injury. Thus, brain PDE9 is localized to preferentially regulate nuclear- and membrane-proximal pools of cGMP, and its function likely changes across the life span.