Phosphodiesterase‐1b deletion confers depression‐like behavioral resistance separate from stress‐related effects in mice

Abstract

Phosphodiesterase-1b (Pde1b) is highly expressed in striatum, dentate gyrus, CA3, and substantia nigra. In a new Floxed Pde1b × CreCMV global knock-out (KO) mouse model we show an immobility resistance phenotype that recapitulates that found in constitutive Pde1b KO mice. We use this new mouse model to show that the resistance to acute stress-induced depression-like phenotype is not the product of changes in locomotor activity or reactivity to other stressors (learned helplessness, novelty suppressed feeding, or dexamethasone suppression), and is not associated with anhedonia using the sucrose preference test. Using tamoxifen inducible Cre, we show that the immobility-resistant phenotype depends on the age of induction. The effect is present when Pde1b is deleted from conception, P0 or P32, but not if deleted as adults (P60). We also mapped regional brain expression of PDE1B protein and of the Cre driver. These data add to the suggestion that PDE1B may be a target for drug development with therapeutic potential in depression alone or in combination with existing antidepressants.

Phosphodiesterase 1b (PDE1B) Regulates Spatial and Contextual Memory in Hippocampus

“…Constitutive (Reed et al, 2002; Siuciak et al, 2007) as well as conditional (Hufgard et al, 2017) PDE1B knockout mice exhibit altered exploratory activity in the open field. We therefore asked if selectively targeting PDE1B in hippocampus of adult mice causes locomotor effects that may confound analysis of a role in memory using the current approach.…”

“…In addition to Schizophrenia, PDE1 inhibitors may have therapeutic benefits in mild-cognitive impairment associated with Parkinson’s disease (Parkinson’s MCI), Alzheimer’s disease, and cognitive deficits in major depressive disorder (MDD; Hufgard et al, 2017). However, additional work will be required to determine the mechanistic and behavioral impact of PDE1 inhibition in the context of disease.…”

A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia

“…For example, PDE1B-deletion mice manifest a compensatory increase in PDE10A in the striatum (Hufgard et al, 2017a). In addition, the immobility-resistant phenotype of PDE1B-deficient mice is detected when the PDE1B gene deletion occurs during postnatal days 0 or 32 but not during adulthood (Hufgard et al, 2017b). Furthermore, PDE1B-deficient mice display spatial learning and memory impairments in the Morris water maze task (Reed et al, 2002), while PDE1 inhibitors improve learning and memory function in several behavioral tasks in mice and rats (Li et al, 2016a;Snyder et al, 2016;Pekcec et al, 2018;McQuown et al, 2019).…”

Sex-dependent effects of amyloidosis on functional network hub topology is associated with downregulated neuronal gene signatures in the APPswe/PSEN1dE9 double transgenic mouse

“…Syndig1l harbors epigenetic CpG-related single nucleotide polymorphisms associated with AD in Hispanic populations (Ma et al, 2024). Pde1b , encoding a phosphodiesterase 1, has been linked to motor activity and spatial learning (Reed et al, 2002), identified in motor control in striatum of transgenic mice of Huntington’s (Hebb et al, 2004) and involved in depression-like behaviors in response to stress in mice (Hufgard et al, 2017). Overexpression of Pde1b in dopamine D1 receptor-containing striatal MSNs attenuated the locomotor response to cocaine in female mice but not males (Teague et al, 2024).…”