Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity

Abstract

Extensive research has uncovered diverse forms of synaptic plasticity and a wide array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cAMP-dependent signaling pathways have been crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of POPDC1 (or BVES), a cAMP effector protein expressed in brain, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as PKA and EPAC, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains. These properties suggest that POPDC1 may have a unique role in cAMP-mediated signaling underlying synaptic plasticity. Our results show that POPDC1 is enriched in hippocampal synaptoneurosomes. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit enhanced long-term potentiation (LTP) induced by a variety of stimulation paradigms, particularly in response to weak stimulation paradigms that in slices from wildtype mice induce only transient LTP. Furthermore, Popdc1 KO mice did not display any further enhancement in forskolin-induced LTP observed following inhibition of phosphodiesterases (PDEs), suggesting a possible modulation of cAMP-PDE signaling by POPDC1. Taken together, these data reveal POPDC1 as a novel player in the regulation of hippocampal synaptic plasticity and as a potential target for cognitive enhancement strategies.

The Role of POPDC Proteins in Cardiac Pacemaking and Conduction

“…POPDC1 is found in different subregions of the hippocampus including CA1 and seems to be particularly enriched in the synaptic membrane fraction, which supports a potential role in modulating synaptic plasticity [115]. Indeed, high-frequency electrical stimulation of hippocampal slices isolated from Popdc1 null mutants showed enhanced LTP, especially in response to a single-train high-frequency electrical stimulation, which suggests that loss of Popdc1 probably reduces the threshold for LTP induction [115]. Pharmacological treatment of hippocampal slices of Popdc1 null mutants with FSK or FSK and IBMX (an unspecific PDE antagonist) differed in their effects on LTP formation.…”

“…PKA activation functions like a gate between transient and persistent forms of LTP [117,118]. POPDC1 is found in different subregions of the hippocampus including CA1 and seems to be particularly enriched in the synaptic membrane fraction, which supports a potential role in modulating synaptic plasticity [115]. Indeed, high-frequency electrical stimulation of hippocampal slices isolated from Popdc1 null mutants showed enhanced LTP, especially in response to a single-train high-frequency electrical stimulation, which suggests that loss of Popdc1 probably reduces the threshold for LTP induction [115].…”

“…Additionally, the overlapping nature of the aforementioned phenotypes suggests that POPDC proteins play a fundamental and essential role in cardiac electrophysiology. Recent work defining the role of POPDC1 in hippocampal long-term potentiation suggests that POPDC proteins' role in membrane biology is not confined to the heart [115]. It is possible that the underlying molecular pathways in which POPDC proteins are involved in hippocampal neurons and cardiac myocytes may be similar or even identical.…”

“…The interaction and complex formation between POPDC1 and PDE4A may also be relevant for the altered hippocampal synaptic plasticity that was recently described for Popdc1 null mutants [115]. Activity-dependent modulation of synaptic plasticity is essential to learning and memory, and its many forms are associated with a complex set of molecular signaling pathways [116].…”

“…Therefore, these results can be interpreted as evidence for a buffering function of POPDC proteins to prevent abnormal levels of cAMP accumulation in cells and thereby ensuring a graded response to different cAMP levels. PKA inhibition blocks enhanced LTP formation in Popdc1 null mutants, which suggests that POPDC proteins similar to its function in cardiac myocytes are probably involved in fine tuning and limiting LTP formation by preventing PKA-driven phosphorylation of target proteins in response to subthreshold LTP-inducing stimuli [115].…”