title: Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum.
abstract: The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum.
authors.affiliation: Departments of Psychiatry, Neurology and Neurotherapeutics and Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Adan
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Departments of Psychiatry, Neurology and Neurotherapeutics and Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Tan
authors.affiliation: Departments of Psychiatry, Neurology and Neurotherapeutics and Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mettlach
authors.affiliation: Departments of Psychiatry, Neurology and Neurotherapeutics and Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Karine
authors.initials: K
authors.lastname: Pozo
authors.affiliation: Departments of Psychiatry, Neurology and Neurotherapeutics and Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.affiliation: Departments of Psychiatry, Neurology and Neurotherapeutics and Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003342:Corpus Striatum / Q000201:enzymology*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D051360:Cyclin-Dependent Kinase 5; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C495906:Cdk5 protein, mouse; D004298:Dopamine