Abstract
Dopamine, a key striatal neuromodulator, increases synaptic strength by promoting surface insertion and/or retention of AMPA receptors (AMPARs). This process is mediated by the phosphorylation of the GluA1 subunit of AMPAR by cyclic nucleotide-dependent kinases, making cyclic nucleotide phosphodiesterases (PDEs) potential regulators of synaptic strength. In this study, we examined the role of phosphodiesterase 2 (PDE2), a medium spiny neuron-enriched and cGMP-activated PDE, in AMPAR trafficking. We found that inhibiting PDE2 resulted in enhancement of dopamine-induced surface GluA1 expression in dopamine receptor 1-expressing medium spiny neurons. Using pharmacological and genetic approaches, we found that inhibition of PDE1 resulted in a decrease in surface AMPAR levels because of the allosteric activation of PDE2. The cross-regulation of PDE1 and PDE2 activities results in counterintuitive control of surface AMPAR expression, making it possible to regulate the directionality and magnitude of AMPAR trafficking.
Highlights
Changes to synaptic strength at corticostriatal synapses regulate the excitability of MSNs,3 resulting in coding for motivated behavior [1, 2]
We have previously shown the involvement of PDE4 [39] in dopamine-mediated AMPA receptors (AMPARs) trafficking in MSNs
Our computational model simulations indicate that the cGMP activation of phosphodiesterase 2 (PDE2) is capable of inducing changes in cAMP levels that are sufficient to decrease AMPAR surface expression
Summary
Changes to synaptic strength at corticostriatal synapses regulate the excitability of MSNs,3 resulting in coding for motivated behavior [1, 2]. We present a novel mechanism of how cGMP may be controlling striatal AMPAR trafficking in response to DA via the cross-regulation of PDEs. We show that increases in cGMP (either by enhancing cGMP production or decreasing cGMP degradation) result in PDE2 activation, leading to a reduction in DA-induced cAMP levels and AMPAR insertion.
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