Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum.

Adan Hernandez,Gabriel Mettlach,James A Bibb,Florian Plattner,Karine Pozo,Chunfeng Tan

doi:10.1038/srep29812

Adan Hernandez, Gabriel Mettlach + Show 4 more

Open Access

https://doi.org/10.1038/srep29812

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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.

Highlights

Striatal circuitry mediates procedural or implicit learning that results in automatized responses, roughly equivalent to habits[1,2,3]
Two forms of long-lasting synaptic plasticity have been described at glutamatergic cortico-striatal synapses, namely long-term depression (LTD) and long-term potentiation (LTP)
The most commonly reported form of cortico-striatal plasticity is LTD that can be induced in response to high-frequency stimulation (HFS) in vitro

Summary

Introduction

Striatal circuitry mediates procedural or implicit learning that results in automatized responses, roughly equivalent to habits[1,2,3]. The dorsolateral striatum receives excitatory glutamatergic input from cortical neurons and consistently the N-methyl-D-aspartic acid (NMDA) glutamate receptor plays an important role in procedural learning task performance[10]. The most commonly reported form of cortico-striatal plasticity is LTD that can be induced in response to high-frequency stimulation (HFS) in vitro. Cdk[5] is a proline-directed serine/threonine kinase that is activated through interaction with its cofactors p35 or p3928 This kinase has been implicated in numerous CNS processes, including cortical layer formation, neurotransmission, and mnemonic functions[29,30]. We further characterize cortico-striatal synaptic plasticity in mice via extracellular field recordings, and assess the role of Cdk[5] in striatal LTP and motor skill learning

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