Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology

Abstract

Motor learning and neuro-adaptations to drugs of abuse rely upon neuronal signaling in the striatum. Cyclin-dependent kinase 5 (Cdk5) regulates striatal dopamine neurotransmission and behavioral responses to cocaine. Although the role for Cdk5 in neurodegeneration in the cortex and hippocampus and in hippocampaldependent learning has been demonstrated, its dysregulation in the striatum has not been examined. Here we show that strong activation of striatal NMDA receptors produced p25, the truncated form of the Cdk5 co-activator p35. Furthermore, inducible overexpression of p25 in the striatum prevented locomotor sensitization to cocaine and attenuated motor coordination and learning. This corresponded with reduced dendritic spine density, increased neuro-inflammation, altered dopamine signaling, and shifted Cdk5 specificity with regard to physiological and aberrant substrates, but no apparent loss of striatal neurons. Thus, dysregulation of Cdk5 dramatically affects striatal-dependent brain function and may be relevant to non-neurodegenerative disorders involving dopamine neurotransmission.p25 ͉ spines ͉ addiction ͉ dopamine ͉ neurodegeneration N euronal signal transduction mediates the regulation of synaptic strength that underlies learning and memory. Dysregulation of synaptic signaling may result in neuropsychiatric and neurological disorders. Striatal medium spiny neurons (MSNs) receive midbrain dopaminergic and cortical glutamatergic input and mediate reward-based and motor learning. Furthermore, numerous psychiatric and neurodegenerative illnesses target striatal function. Study of the effects of dysregulation of signaling mechanisms that integrate striatal glutamate and dopamine neurotransmission may provide an understanding of the etiology of such disorders.Cdk5 regulates dopamine neurotransmission (1, 2) and striatal neuron excitability (1, 3). Cocaine targets dopamine neurotransmission by elevating synaptic dopamine levels. Cdk5 modulates the effects of cocaine, including its ability to induce neuroadaptations in signaling, behavior, and neuronal morphology (3-7). Cdk5 also functions in synaptic plasticity and learning (8-10) in hippocampus. Striatal synaptic plasticity involves changes in Cdk5-dependent regulation of dopamine signaling (11), and conditional loss of Cdk5 in the striatum lowers the threshold dose required for cocaine to induce a place preference (3). However, dysregulation of Cdk5 in the striatum and its effects on striatal-mediated behavior and learning has remained largely unexplored.Cdk5 activity is dependent on association with its cofactor p35. Cdk5 may be regulated through auto-phosphorylation of p35 (12, 13) and glutamatergic Ca 2ϩ signaling (14, 15). However, the most prominent feature of Cdk5 regulation may be its hyperactivation upon removal of the first 100 amino acids of p35 by the Ca 2ϩ -dependent protease calpain. The resulting Cdk5/p25 complex engenders aberrant activity and is neurotoxic. P25 overexpression in mouse hippocampus and cortex results in dramatic neurodegenera...

Ischemic Stroke Injury Is Mediated by Aberrant Cdk5

“…Cdk5/p25 may represent a more soluble form of the kinase and DARPP-32, as a physiological substrate, is found in striatal cytoplasm. Nevertheless, these effects are consistent with those observed when transgenic p25 overexpression is induced in striatum (Meyer et al, 2008).…”

“…Bright-field microcopy was conducted using an Olympus BX-51 microscope. Fluorescent images were captured by laser scanning confocal microscopy (Meyer et al, 2008).…”

Constitutive Knockout of Kalirin-7 Leads to Increased Rates of Cocaine Self-Administration

“…This suggests that Kal7 KO mice have increased sensitivity to the rewarding properties of cocaine, in line with the increased locomotor sensitization response noted previously (Kiraly et al, 2010b). A connection between failure to upregulate NAc spine density after cocaine and increased locomotor sensitization and food-seeking was noted in Kal7 KO mice and in mice lacking Cdk5, SynCAM1, Mef2, or Dnmt3a (Norrholm et al, 2003;Benavides et al, 2007;Meyer et al, 2008;Pulipparacharuvil et al, 2008;LaPlant et al, 2010;Giza et al, 2013;Rothenfluh and Cowan, 2013). As other models are examined, it will be interesting to see the possible connection between blunted spine plasticity, heightened locomotor sensitization, and increased self-administration.…”

Mechanisms of Psychostimulant-Induced Structural Plasticity

“…This provides a somewhat parallel mechanism by which both Cdk5 and MEF2 can ultimately regulate dendritic morphology. Unexpectedly, both inhibition of Cdk5 and activation of MEF2 enhance behavioral responses to cocaine administration, even though they block cocaine-induced NAc dendritic spine formation (Bibb et al 2001;Benavides et al 2007;Taylor et al 2007;Meyer et al 2008;Pulipparacharuvil et al 2008). This paradox suggests that the central dogma whereby NAc dendritic spine density translates to behavioral sensitization is not completely correct.…”