PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity

Abstract

Synapses are the functional units of the brain. They form specific contact points that drive neuronal communication and are highly plastic in their strength, density, and shape. A carefully orchestrated balance between synaptogenesis and synaptic pruning, i.e., the elimination of weak or redundant synapses, ensures adequate synaptic density. An imbalance between these two processes lies at the basis of multiple neuropathologies. Recent evidence has highlighted the importance of glia-neuron interactions in the synaptic unit, emphasized by glial phagocytosis of synapses and local excretion of inflammatory mediators. These findings warrant a closer look into the molecular basis of cell-signaling pathways in the different brain cells that are related to synaptic plasticity. In neurons, intracellular second messengers, such as cyclic guanosine or adenosine monophosphate (cGMP and cAMP, respectively), are known mediators of synaptic homeostasis and plasticity. Increased levels of these second messengers in glial cells slow down inflammation and neurodegenerative processes. These multi-faceted effects provide the opportunity to counteract excessive synapse loss by targeting cGMP and cAMP pathways in multiple cell types. Phosphodiesterases (PDEs) are specialized degraders of these second messengers, rendering them attractive targets to combat the detrimental effects of neurological disorders. Cellular and subcellular compartmentalization of the specific isoforms of PDEs leads to divergent downstream effects for these enzymes in the various central nervous system resident cell types. This review provides a detailed overview on the role of PDEs and their inhibition in the context of glia-neuron interactions in different neuropathologies characterized by synapse loss. In doing so, it provides a framework to support future research towards finding combinational therapy for specific neuropathologies.

Keywords: cell-signaling; glia-neuron; neurodegeneration; phosphodiesterase; synapses.

Figure 1

Overview of the proven effective PDE inhibition on different cell types involved in synapse maintenance or loss in the physiological state (A) or neurodegeneration (B). Resident neuroglial cells have dual roles in the physiological state (A), highlighted by the presence of pro-(red) inflammatory and anti-(green) inflammatory cytokines. The positive effects on individual synapses are shown above the dotted line, while detrimental effects are shown below. In neurodegenerative pathologies (B), in which disruption of the blood-brain-barrier is common, the resident neuroglia become activated, and patrolling macrophages (pale green) extravasate into the central nervous system and intermingle with microglia (bright blue). Local upregulation of complement proteins (C1q and C3b) leads to targeted clearance of synapses by microglia and astrocytes (bright green). Inhibition of various PDEs (PDEXi) has been found to influence synaptic plasticity directly in neurons and indirectly via glial cells by skewing them toward an anti-inflammatory phenotype and promoting transcription factors to express for instance Brain-Derived Neurotrophic Factor (BDNF) from oligodendrocytes (purple). Images were modified from Reactome icon library and Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License .