Enhanced Remote Long-Term Social Memory Despite an Absence of Any Recent Long-Term Memory for That Same Event

Abstract

System consolidation (SC) 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 SC. PDE11A4; which degrades cAMP/cGMP and regulates glutamate signaling and protein synthesis; is preferentially expressed in neurons of CA1; the subiculum; and the adjacently connected amygdalohippocampal region. Deletion of PDE11A enhances remote LTM for social odor recognition and social transmission of food preference (STFP) despite eliminating/silencing recent LTM for those same social events. Measurement of Arc mRNA; a surrogate marker of neuronal activation; suggests the impaired recent LTM for STFP observed in Pde11 KO mice corresponds with decreased activation of ventral CA1 relative to wild-type (WT) littermates; whereas; the enhanced remote LTM for STFP observed in Pde11a KO 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 KO mice may be related to an upregulation of the NMDA receptor subunits NR1 and NR2A. Viral restoration of PDE11A4 to vCA1 alone is sufficient to reverse both the LTM phenotypes and upregulation of NR1 exhibited by Pde11a KO mice. Together our findings suggest remote LTM can be decoupled from recent LTM and may have relevance for cognitive deficits associated with temporal lobe epilepsy or transient global amnesia.