Phosphodiesterase 11A (PDE11A), Enriched in Ventral Hippocampus Neurons, is Required for Consolidation of Social but not Nonsocial Memories in Mice

Abstract

The capacity to form long-lasting social memories is critical to our health and survival. cAMP signaling in the ventral hippocampal formation (VHIPP) appears to be required for social memory formation, but the phosphodiesterase (PDE) involved remains unknown. Previously, we showed that PDE11A, which degrades cAMP and cGMP, is preferentially expressed in CA1 and subiculum of the VHIPP. Here, we determine whether PDE11A is expressed in neurons where it could directly influence synaptic plasticity and whether expression is required for the consolidation and/or retrieval of social memories. In CA1, and possibly CA2, PDE11A4 is expressed throughout neuronal cell bodies, dendrites (stratum radiatum), and axons (fimbria), but not astrocytes. Unlike PDE2A, PDE9A, or PDE10A, PDE11A4 expression begins very low at postnatal day 7 (P7) and dramatically increases until P28, at which time it stabilizes to young adult levels. This expression pattern is consistent with the fact that PDE11A is required for social long-term memory (LTM) formation during adolescence and adulthood. Male and female PDE11 knockout (KO) mice show normal short-term memory (STM) for social odor recognition (SOR) and social transmission of food preference (STFP), but no LTM 24 h post training. Importantly, PDE11A KO mice show normal LTM for nonsocial odor recognition. Deletion of PDE11A may impair memory consolidation by impairing requisite protein translation in the VHIPP. Relative to WT littermates, PDE11A KO mice show reduced expression of RSK2 and lowered phosphorylation of S6 (pS6–235/236). Together, these data suggest PDE11A is selectively required for the proper consolidation of recognition and associative social memories.

PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain

“…Previously we showed that PDE11A expression is minimal at postnatal day 7 but dramatically increases to young adulthood levels between postnatal day 21–28 (Hegde et al, 2016). Social approach behaviors become reliably measurable in the mouse around postnatal day 19 (Laviola et al, 1994; Fairless et al, 2012), suggesting PDE11A mutant mice might exhibit social approach deficits early in adolescence.…”

“…PDE11A knockout (KO) mice were originally developed by Deltagen (San Mateo, CA, USA), and are maintained on a mixed C57BL/6J-C57BL/6N-129S6 background, as previously described (Kelly et al, 2010; Hegde et al, 2016). PDE11A mice were bred onsite in heterozygous (HT) × HT matings, with same-sex wild-type (WT), HT, and knockout(KO) littermates weaned together into the same cage at P28 (3–5/cage; but see “mouse psychiatrist” assay below).…”

“…As previously described (Kelly et al, 2010; Hegde et al, 2016), mice were individually placed in a clean home cage and allowed to explore 3 wooden beads—2 from their home cage and 1 from the cage of a novel mouse strain (C57BL/6J, BALB/cJ, 129S6/SvEv). During a 2-min memory test 24 h after training, mice were again presented with 3 beads: home cage, bead from training, and a bead from another strain.…”

“…1A) (Kelly et al, 2010, 2014; Kelly, 2014, 2015; Hegde et al, 2016; Pathak et al, in press) and little to no expression in peripheral organs (c.f., (Kelly, 2015)). PDE11A has been genetically and/or functionally associated with clinical phenotypes related to changes in social function, including major depressive disorder (Wong et al, 2006; Cabanero et al, 2009; Luo et al, 2009), suicide risk (an inactivating mutation, (Coon et al, 2013)), and lithium responsivity (Couzin, 2008; Kelsoe, 2010; Mertens et al, 2015; Pathak et al, in press).…”

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

“…Interestingly, subsequent preclinical studies have confirmed that although PDE11 KO mice exhibit normal short-term memory for social odor recognition and social transmission of food preference, they show impaired long-term memory. At the same time, PDE11A KO mice showed normal long-term memory for nonsocial odor recognition [104,105]. Therefore, PDE11 seems to fulfill a special role in the consolidation of social memories.…”