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

Abstract

Augmentation of cyclic nucleotide signaling through inhibition of phosphodiesterase (PDE) activity has long been understood to enhance memory. Efforts in this domain have focused predominantly on PDE4, a cAMP-specific phosphodiesterase implicated in consolidation. But less is known about the function of other PDEs expressed in neuroanatomical regions critical to memory. The PDE1 isoforms are the only PDEs to regulate neuronal cAMP and cGMP levels in a Ca2+/Calmodulin (CaM) dependent manner. Here, we show that knock-down of PDE1B in hippocampus of adult mice enhances contextual and spatial memory without effect on non-cognitive behaviors. Pharmacological augmentation of memory in rats was observed with a selective inhibitor of PDE1 dosed before and immediately after training, but not with drug dosed either 1 h after training or before recall. Our data clearly demonstrate a role for the PDE1B isoforms as negative regulators of memory, and they implicate PDE1 in an early phase of consolidation, but not retrieval. Inhibition of PDE1B is a promising therapeutic mechanism for treating memory impairment.

Vinpocetine and Ischemic Stroke

“…From these points, the mechanisms of PSCD remain obscure due to overlapping between neuro-pathological data and findings of PSCD and Alzheimer disease [77]. VPN improves cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE-1with augmentation of cAMP/cGMP ratio, enhancement of cholinergic neurotransmission and inhibition of neuronal IKK/NF-kB [78,79]. It has been noticed by Bitner study that both cAMP and cGMP activate PKA and cAMP-response element-binding protein (CREP) which improves synaptic plasticity and neurogenesis through up-regulation of BDNF.…”

“…cAMP/cGMP/CREP pathway increases early and late long-term potentiation of memory [80] Besides, other PDE inhibitors like sildenafil (PDE-5 inhibitors) and cilostazol (PDE-3 inhibitor) also improve cognitive function and PSCD [81]. Recently, McQuown et al illustrated that VPN improves memory function mainly through inhibition of PDE-1B isoform as it mainly located in regions with high dopaminergic neurotransmission such as the prefrontal cortex, striatum and dentate gyrus [78]. Therefore, VPN is an effective therapy in rehabilitation of cognitive, memory deficit and PSCD through modulation of inflammatory changes and enhancement of neuronal cAMP/cGMP in post-stroke survivors [82].…”

Role of vinpocetine in ischemic stroke and poststroke outcomes: A critical review

“…[89] VPN improves cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE-1 with augmentation of cAMP/cGMP ratio, enhancement of cholinergic neurotransmission, and inhibition of neuronal IKK/NF-κB. [90,91] It has been perceived by Bitner study that both cAMP and cGMP activate PKA-response element-binding protein (CREP) improves synaptic plasticity and neurogenesis through upregulation of BDNF. cAMP/cGMP/CREP pathway increases early and late long-term potentiation of memory.…”

“…[93] Recently, McQuown et al illustrated that VPN improves memory function mainly through inhibition of PDE-1B isoform, as it mainly located in regions with high dopaminergic neurotransmission such as the prefrontal cortex, striatum, and dentate gyrus. [90] Therefore, VPN is an effective therapy in rehabilitation of cognitive, memory deficit, and PSCD through modulation of inflammatory changes and enhancement of neuronal cAMP/cGMP in poststroke survivors. [94]…”

Caesalpinia sappan L. Wood is a Potential Source of Natural Phosphodiesterase-1 Inhibitors

“…The isoform used as a protein target in this docking experiment was associated with spatial and contextual memory regulatory function in the hippocampus. 25 Target protein crystals were acquired from Protein Data Bank (RCSB PDB, https://www.rcsb.org/). The 3D structures of 28 tested compounds were obtained from SMILES ID in PubChem (https://www.pubchem.ncbi.nlm.nih.gov/).…”