Pde11a

Kelly, Michy P.

doi:10.1007/978-3-319-67199-4_101747

Cited by 9 publications

(18 citation statements)

References 89 publications

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“…For example, Pde11a deletion would be expected to increase cAMP-PKA activity [9], which could increase phosphorylation of cofilin (e.g., [41]) and thus promote forgetting [42]. In addition, Pde11a deletion would be expected to increase cyclic guanosine monophosphate (cGMP) [43] and reduce phosphorylation of CamKIIa [17], both of which could lead to synaptic depotentiation or a failure to maintain long-term changes in synaptic plasticity (cf. [44]).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…There are eleven families of 3’,5’-cyclic nucleotide phosphodiesterases (PDEs) that are the only known enzymes to hydrolyze 3’,5’-cyclic adenosine monophosphate (cAMP) and 3’,5’-cyclic guanosine monophosphate (cGMP), and their expression across subcellular compartments differs between families [7]. For example, some PDEs are expressed more in the cytosol than the membrane (e.g., PDE11A), while others are more highly expressed in the membrane versus cytosol (including PDE2A, PDE9A and PDE10A [8, 9]). Due to the fact that PDEs are localized to specific subcellular domains, they are able to regulate individual pools or nanodomains of cyclic nucleotide signaling [7].…”

Section: Introductionmentioning

confidence: 99%

“…PDE11A is encoded by a single gene and has four isoforms [9-12, 14]. While protein for PDE11A4—the isoform expressed in brain—is found across all subcellular compartments, it is particularly enriched in the cytosolic versus membrane and nuclear compartments [8]. The PDE11A catalytic domain is located within the C-terminal region, which is common to all isoforms, while the N-terminal region serves a regulatory function and is unique to each isoform (c.f., [8, 19]).…”

Section: Introductionmentioning

confidence: 99%

Biologic that disrupts PDE11A4 homodimerization in hippocampus CA1 reverses age-related proteinopathies in PDE11A4 and cognitive decline of social memories

Pilarzyk

Capell

Rips-Goodwin

et al. 2022

Preprint

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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.

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“…PDE11A4 exists as a homodimer and degrades both 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) ( Kelly, 2015 ) and is particularly enriched in cell bodies, dendrites and axons of neurons of the superficial layer of CA1, the subiculum, and the adjacently connected amygdalohippocampal area of the ventral hippocampal formation (VHIPP; aka anterior hippocampal formation in primates) ( Kelly et al, 2010 ; Hegde et al, 2016a ). Low levels of PDE11A4 expression can be found in neurons of the dorsal hippocampus (DHIPP), dorsal root ganglion, and spinal cord, but no protein expression has been found to originate from glia, other brain regions, or over 20 peripheral organs ( Kelly et al, 2010 ; Kelly, 2015 ; Hegde et al, 2016a ; Pathak et al, 2017 ; Kelly, 2018b ). Interestingly, expression of PDE11A4 in the hippocampus dramatically increases over the lifespan, suggesting PDE11A function may evolve with age ( Kelly et al, 2014 ; Hegde et al, 2016a ).…”

Section: Introductionmentioning

confidence: 99%

“…Social experiences sculpt subsequent social behaviors, and PDE11A4 appears to be a critical neurobiological mechanism regulating this feedforward cycle. Upon biochemical fractionation of the hippocampus, about half of PDE11A4 is found in the soluble fraction, with the other half split between the nuclear and membrane fractions ( Kelly, 2018b ). We find that it is membrane PDE11A4 that is particularly important in regulating social behaviors in both young adult and old mice ( Hegde et al, 2016b ; Smith et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of PDE11A4 in Social Isolation-Induced Changes in Intracellular Signaling and Neuroinflammation

et al. 2021

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Phosphodiesterase 11A (PDE11A), an enzyme that degrades cyclic nucleotides (cAMP and cGMP), is the only PDE whose mRNA expression in brain is restricted to the hippocampal formation. Previously, we showed that chronic social isolation changes subsequent social behaviors in adult mice by reducing expression of PDE11A4 in the membrane fraction of the ventral hippocampus (VHIPP). Here we seek extend these findings by determining 1) if isolation-induced decreases in PDE11A4 require chronic social isolation or if they occur acutely and are sustained long-term, 2) if isolation-induced decreases occur uniquely in adults (i.e., not adolescents), and 3) how the loss of PDE11 signaling may increase neuroinflammation. Both acute and chronic social isolation decrease PDE11A4 expression in adult but not adolescent mice. This decrease in PDE11A4 is specific to the membrane compartment of the VHIPP, as it occurs neither in the soluble nor nuclear fractions of the VHIPP nor in any compartment of the dorsal HIPP. The effect of social isolation on membrane PDE11A4 is also selective in that PDE2A and PDE10A expression remain unchanged. Isolation-induced decreases in PDE11A4 expression appear to be functional as social isolation elicited changes in PDE11A-relevant signal transduction cascades (i.e., decreased pCamKIIα and pS6-235/236) and behavior (i.e., increased remote long-term memory for social odor recognition). Interestingly, we found that isolation-induced decreases in membrane PDE11A4 correlated with increased expression of interleukin-6 (IL-6) in the soluble fraction, suggesting pro-inflammatory signaling for this cytokine. This effect on IL-6 is consistent with the fact that PDE11A deletion increased microglia activation, although it left astrocytes unchanged. Together, these data suggest that isolation-induced decreases in PDE11A4 may alter subsequent social behavior via increased neuroinflammatory processes in adult mice.

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Pde11a

Cited by 9 publications

References 89 publications

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

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

Biologic that disrupts PDE11A4 homodimerization in hippocampus CA1 reverses age-related proteinopathies in PDE11A4 and cognitive decline of social memories

The Role of PDE11A4 in Social Isolation-Induced Changes in Intracellular Signaling and Neuroinflammation

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