Abstract

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.

Highlights

  • To determine whether this isolation-induced decrease in PDE11A4 protein required chronic social isolation or if it occurred acutely and was sustained long term, we devised an isolation timeline consisting of group housed (GH) and isolated adult mice that were single-housed for 1 h (SH), 1 day (SD), 1 week (SW), or 1 month (SM)

  • Compared to group-housed controls, both acute and chronic social isolation in adult C57BL6/J was sufficient to decrease PDE11A4 protein expression in the membrane compartment of the ventral hippocampal formation (VHIPP) (Figure 1A). This loss of VHIPP membrane PDE11A4 was specific to this compartment as there was no change in PDE11A4 expression in the VHIPP soluble fraction, VHIPP nuclear fraction (Figures 1B,C) nor any compartments of the dorsal hippocampus (DHIPP) (Figures 1E–G)

  • Social isolation had no effect on membrane expression of PDE2A or PDE10A in VHIPP, suggesting that the isolation-induced decrease of PDE11A4 is selective (Figures 1H,I)

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Summary

Introduction

Various phosphodiesterase (PDE) families are known to influence social behaviors (Sano et al, 2008; Grauer et al, 2009a; Alexander et al, 2016; Gurney et al, 2017; Maurin et al, 2018; Enomoto et al, 2019) or neuroinflammation (Sebastiani et al, 2006; Peixoto et al, 2015; Schwenkgrub et al, 2017; Tibbo and Baillie, 2020; Ponsaerts et al, 2021); but evidence suggests the PDE11A family may be a key regulator of both. 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). While little has been characterized of the signaling pathways lying up or downstream of PDE11A4, we have shown that PDE11A4 regulates glutamatergic and calcium/calmodulin-dependent kinase II (CamKII) signaling as well as protein synthesis (Kelly et al, 2010; Kelly et al, 2014; Hegde et al, 2016a; Pilarzyk et al, 2019). It may not be surprising that PDE11A4 is proving to be a key regulator of social memory and social interactions (Kelly et al, 2010; Hegde et al, 2016a; Hegde et al, 2016b; Pilarzyk et al, 2019; Smith et al, 2021)

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