Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum

Abstract

Dopaminergic and glutamatergic neurotransmissions in the striatum play an essential role in motor-and reward-related behaviors. Dysfunction of these neurotransmitter systems has been found in Parkinson's disease, schizophrenia, and drug addiction. Cyclindependent kinase 5 (CDK5) negatively regulates postsynaptic signaling of dopamine in the striatum. This kinase also reduces the behavioral effects of cocaine. Here we demonstrate that, in addition to a postsynaptic role, CDK5 negatively regulates dopamine release in the striatum. Inhibitors of CDK5 increase evoked dopamine release in a way that is additive to that of cocaine. This presynaptic action of CDK5 also regulates glutamatergic transmission. Indeed, inhibition of CDK5 increases the activity and phosphorylation of N-methyl-D-aspartate receptors, and these effects are reduced by a dopamine D1 receptor antagonist. Using mice with a point mutation of the CDK5 site of the postsynaptic protein DARPP-32 (dopamine-and cAMP-regulated phosphoprotein, molecular mass of 32 kDa), in the absence or in the presence of a dopamine D1 receptor antagonist, we provide evidence that CDK5 inhibitors potentiate dopaminergic transmission at both presynaptic and postsynaptic locations. These findings, together with the known ability of CDK5 inhibitors to prevent degeneration of dopaminergic neurons, suggest that this class of compounds could potentially be used as a novel treatment for disorders associated with dopamine deficiency, such as Parkinson's disease.T he striatum plays a crucial role in processing information related to motor function and reward-and goal-oriented behaviors. The striatum integrates dopaminergic inputs from midbrain nuclei and glutamatergic inputs from the neocortex and the thalamus (1). The pathophysiology of several psychiatric and neurological disorders, including Parkinson's disease, schizophrenia, and drug addiction, arises from improper function of the striatum because of a loss of dopamine-producing neurons or an imbalance of dopamine and glutamate transmissions. A more complete understanding of the mechanisms that regulate dopamine͞glutamate interactions in the striatum is likely to improve our understanding of the physiology of the striatum under normal and pathological conditions. Recent biochemical evidence showed that the Ser͞Thr protein kinase cyclin-dependent kinase 5 (CDK5) inhibits postsynaptic dopaminergic signaling in the striatum. Indeed, by phosphorylating the striatal-enriched postsynaptic protein DARPP-32 (dopamine-and cAMP-regulated phosphoprotein, molecular mass of 32 kDa) at Thr 75 and thereby converting this protein into an inhibitor of cAMP-dependant protein kinase A (PKA), CDK5 counteracts dopamine D1 receptor͞PKA-mediated signaling (2, 3). In addition, behavioral effects of cocaine are enhanced by striatal infusion of CDK5 inhibitors (4). Thus, CDK5 seems to play a major role in regulating postsynaptic dopamine signaling in the striatum. This study was therefore undertaken to address whether this protein kinase also regulates ...

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“…[2][3][4][5][6] Unlike other cell cycle-promoting members of Cdk family, Cdk5 kinase primarily modulates neuroskeletal dynamics in postmitotic neurons. 3,7,8 Cdk5 plays an essential role in both developing and adult neurons, including neuronal migration, 9,10 axon guidance, 11 neurite outgrowth, 7 dynamics of synaptic structure, [12][13][14] neurotransmission, 15,16 and neuronal secretion. 17 Cdk5 null mice suffer perinatal mortality, with severe defects in neuronal migration and laminar configuration in the cerebral cortex.…”

Treatment Enhances Ultradian Rhythms of CSF Monoamine Metabolites in Patients with Major Depressive Episodes

“…Activators of 5-HT 7 include a variety of antidepressants (Lovenberg et al, 1993;Mullins et al, 1999). Periodic cell function determinants, possibly including cyclin-dependant kinases, may point to novel treatments for psychiatric disorders (Chergui et al, 2004). 'Healthy' oscillatory function would appear to be important since neurotrophic activations are enhanced by oscillations in transmitter levels (Nishi et al, 2000).…”

Cdk5 Modulates Cocaine Reward, Motivation, and Striatal Neuron Excitability

“…This kinase regulates numerous aspects of neuronal function, including cAMP and Ca 2ϩ signal transduction cascades (for review, see Bibb, 2003), presynaptic machinery (Tan et al, 2003;Tomizawa et al, 2003;Evans and Cousin, 2007), and synaptic plasticity (Fischer et al, 2005;Centonze et al, 2006;. In the striatum, Cdk5 controls dopamine neurotransmission through the regulation of the protein phosphatase-1 inhibitor, DARPP-32 (Bibb et al, 1999), as well as presynaptic components of dopamine synthesis and release (Chergui et al, 2004;Kansy et al, 2004;Moy and Tsai, 2004). Thus, Cdk5 may regulate reward-related behaviors through numerous neurobiochemical pathways in the reward circuitry.…”