title: The Cdk5 inhibitor Roscovitine increases LTP induction in corticostriatal synapses.
abstract: In corticostriatal synapses, LTD (long-term depression) and LTP (long-term potentiation) are modulated by the activation of DA (dopamine) receptors, with LTD being the most common type of long-term plasticity induced using the standard stimulation protocols. In particular, activation of the D1 signaling pathway increases cAMP/PKA (protein kinase A) phosphorylation activity and promotes an increase in the amplitude of glutamatergic corticostriatal synapses. However, if the Cdk5 (cyclin-dependent kinase 5) phosphorylates the DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) at Thr75, DARPP-32 becomes a strong inhibitor of PKA activity. Roscovitine is a potent Cdk5 inhibitor; it has been previously shown that acute application of Roscovitine increases striatal transmission via Cdk5/DARPP-32. Since DARPP-32 controls long-term plasticity in the striatum, we wondered whether switching off CdK5 activity with Roscovitine contributes to the induction of LTP in corticostriatal synapses. For this purpose, excitatory population spikes and whole cell EPSC (excitatory postsynaptic currents) were recorded in striatal slices from C57/BL6 mice. Experiments were carried out in the presence of Roscovitine (20 μM) in the recording bath. Roscovitine increased the amplitude of excitatory population spikes and the percentage of population spikes that exhibited LTP after HFS (high-frequency stimulation; 100Hz). Results obtained showed that the mechanisms responsible for LTP induction after Cdk5 inhibition involved the PKA pathway, DA and NMDA (N-methyl-D-aspartate) receptor activation, L-type calcium channels activation and the presynaptic modulation of neurotransmitter release.
authors.forename: Jorge
authors.initials: J
authors.lastname: Miranda-Barrientos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nieto-Mendoza
authors.affiliation: *Unidad de Biomedicina, FES-Iztacala, UNAM, México.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hernández-Echeagaray
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects*; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000077546:Roscovitine; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D020746:Calcium Channels, L-Type; D047428:Protein Kinase Inhibitors; D011687:Purines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D000077546:Roscovitine; D018698:Glutamic Acid; D051360:Cyclin-Dependent Kinase 5; D017868:Cyclic AMP-Dependent Protein Kinases; C495906:Cdk5 protein, mouse