Search

Age-related proteinopathies in phosphodiesterase 11A (PDE11A), an enzyme that degrades 3’,5’-cAMP/cGMP and is enriched in the ventral hippocampal formation (VHIPP), drive age-related cognitive decline (ARCD) of social memories. In the VHIPP, age-related increases in PDE11A4 occur specifically within the membrane compartment and ectopically accumulate in filamentous structures termed ghost axons. Previous in vitro studies show that disrupting PDE11 homodimerization by expressing an isolated PDE11A-GAFB domain, which acts as a “negative sink” for monomers, selectively degrades membrane-associated PDE11A4 and prevents the punctate accumulation of PDE11A4. Therefore, we determined if disrupting PDE11A4 homodimerization in vivo via the expression of an isolated PDE11A4-GAFB domain would be sufficient to reverse 1) age-related accumulations of PDE11A4 in VHIPP ghost axons and 2) ARCD of social memories. Indeed, in vivo lentiviral expression of the isolated PDE11A4-GAFB domain in hippocampal CA1 reversed the age-related accumulation of PDE11A4 in ghost axons, reversed ACRD of social transmission of food preference memory (STFP), and improved remote long-term memory for social odor recognition (SOR) without affecting memory for non-social odor recognition. In vitro studies suggest that disrupting homodimerization of PDE11A4 does not directly alter the catalytic activity of the enzyme but may reverse age-related decreases in cGMP by dispersing the accumulation of the enzyme independently of other intramolecular mechanisms previously established to disperse PDE11A4 (e.g., phosphorylation of PDE11A4 at serine 162). Altogether, these data suggest that a biologic designed to disrupt PDE11A4 homodimerization may serve to ameliorate age-related deficits in hippocampal cyclic nucleotide signaling and subsequent ARCD of remote social memory. more...

In humans, associative memories are more susceptible to age-related cognitive decline (ARCD) than are recognition memories. Reduced cAMP/cGMP signaling in the hippocampus may contribute to ARCD. Here, we found that both aging and traumatic brain injury-associated dementia increased the expression of the cAMP/cGMP-degrading enzyme phosphodiesterase 11A (PDE11A) in the human hippocampus. Further, age-related increases in hippocampal PDE11A4 mRNA and protein were conserved in mice, as was the increased vulnerability of associative versus recognition memories to ARCD. Interestingly, mouse PDE11A4 protein in the aged ventral hippocampus (VHIPP) ectopically accumulated in the membrane fraction and filamentous structures we term "ghost axons." These age-related increases in expression were driven by reduced exoribonuclease-mediated degradation of PDE11A mRNA and increased PDE11A4-pS117/pS124, the latter of which also drove the punctate accumulation of PDE11A4. In contrast, PDE11A4-pS162 caused dispersal. Importantly, preventing age-related increases in PDE11 expression via genetic deletion protected mice from ARCD of short-term and remote long-term associative memory (aLTM) in the social transmission of food preference assay, albeit at the expense of recent aLTM. Further, mimicking age-related overexpression of PDE11A4 in CA1 of old KO mice caused aging-like impairments in CREB function and remote social-but not non-social-LTMs. RNA sequencing and phosphoproteomic analyses of VHIPP identified cGMP-PKG-as opposed to cAMP-PKA-as well as circadian entrainment, glutamatergic/cholinergic synapses, calcium signaling, oxytocin, and retrograde endocannabinoid signaling as mechanisms by which PDE11A deletion protects against ARCD. Together, these data suggest that PDE11A4 proteinopathies acutely impair signaling in the aged brain and contribute to ARCD of social memories. more...

Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability to react with various biological molecules including DNA and proteins, which can greatly impede key processes such as replication and transcription and lead to DNA damage. As such AA is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous in vitro studies have shown that AA generates bulky adducts on DNA, with signature guanine-centered (GG→TT) mutations. However, due to its weak mutagenicity, short chemical half-life, and the absence of powerful genetic assays, there is considerable variability in reporting the mutagenic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA treatment is highly mutagenic to cells and leads to strand-biased mutations on guanines (G→T) at a high frequency on single stranded DNA (ssDNA). We further demonstrate that AA-derived mutations occur through lesion bypass on ssDNA by the translesion polymerase Polζ. Finally, we describe a unique mutation signature for AA, which we then identify in several whole-genome and -exome sequenced cancers, particularly those associated with alcohol consumption. Our study proposes a key mechanism underlying carcinogenesis by acetaldehyde—mutagenesis of single-stranded DNA. more...

Although the physical and mental benefits of friendships are clear, the neurobiological mechanisms driving mutual social preferences are not well understood. Studies in humans suggest friends are more genetically similar, particularly for targets within the 3',5'-cyclic adenosine monophosphate (cAMP) cascade. Unfortunately, human studies can not provide conclusive evidence for such a biological driver of friendship given that other genetically related factors tend to co-segregate with friendship (e.g., geographical proximity). As such, here we use mice under controlled conditions to test the hypothesis that homophily in the cAMP-degrading enzyme phosphodiesterase 11A4 (PDE11A4) can dictate mutual social preference. Using C57BL/6J and BALB/cJ mice in two different behavioral assays, we showed that mice with two intact alleles of Pde11a prefer to interact with Pde11 wild-type (WT) mice of the same genetic background over knockout (KO) mice or novel objects; whereas, Pde11 KO mice prefer to interact with Pde11 KO mice over WT mice or novel objects. This mutual social preference was seen in both adult and adolescent mice, and social preference could be eliminated or artificially elicited by strengthening or weakening PDE11A homodimerization, respectively. Stereotactic delivery of an isolated PDE11A GAF-B domain to the mouse hippocampus revealed the membrane-associated pool of PDE11A-cAMP-CREB signaling specifically within the CA1 subfield of hippocampus is most critical for regulating social preference. Our study here not only identifies PDE11A homophily as a key driver of mutual social preference across the lifespan, it offers a paradigm in which other mechanisms can be identified in a controlled fashion. more...

Summary 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. more...

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. more...