Phosphodiesterase 1 Bridges Glutamate Inputs with NO-and Dopamine-Induced Cyclic Nucleotide Signals in the Striatum

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

  • Dahdjim B. Betolngar
  • Élia Mota
  • Arne Fabritius
  • Jacob Nielsen
  • Hougaard, Charlotte Ørsted
  • Claus T. Christoffersen
  • Jun Yang
  • Jan Kehler
  • Oliver Griesbeck
  • Liliana R.V. Castro
  • Pierre Vincent

The calcium-regulated phosphodiesterase 1 (PDE1) family is highly expressed in the brain, but its functional role in neurones is poorly understood. Using the selective PDE1 inhibitor Lu AF64196 and biosensors for cyclic nucleotides including a novel biosensor for cGMP, we analyzed the effect of PDE1 on cAMP and cGMP in individual neurones in brain slices from male newborn mice. Release of caged NMDA triggered a transient increase of intracellular calcium, which was associated with a decrease in cAMP and cGMP in medium spiny neurones in the striatum. Lu AF64196 alone did not increase neuronal cyclic nucleotide levels, but blocked the NMDA-induced reduction in cyclic nucleotides indicating that this was mediated by calcium-activated PDE1. Similar effects were observed in the prefrontal cortex and the hippocampus. Upon corelease of dopamine and NMDA, PDE1 was shown to down-regulate the D1-receptor mediated increase in cAMP. PDE1 inhibition increased long-term potentiation in rat ventral striatum, showing that PDE1 is implicated in the regulation of synaptic plasticity. Overall, our results show that PDE1 reduces cyclic nucleotide signaling in the context of glutamate and dopamine coincidence. This effect could have a therapeutic value for treating brain disorders related to dysfunctions in dopamine neuromodulation.

TidsskriftCerebral Cortex
Udgave nummer12
Sider (fra-til)5022-5036
Antal sider15
StatusUdgivet - 2019
Eksternt udgivetJa

Bibliografisk note

Funding Information:
Lundbeck A/S and by the "Investissements d'Avenir" program managed by the ANR under reference ANR-11-IDEX-0004-02.

Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:

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