Cdk5 is a proline-directed kinase that regulates many aspects of neuronal function including neuronal migration, axonal and synaptic development, synaptic plasticity, secretion, and cell adhesion.129 Cdk5 is strongly expressed throughout the cortex, thalamus, and amygdala, and moderately expressed in the midbrain, VTA, and NAc.6 Cdk5 is inactive alone and requires dimerization with a partner protein, p35, p39, or p67, for activity. Due to restricted expression of these partner proteins, Cdk5 activity is primarily localized to synapses of mature neurons and growth cones of developing neurons. Cdk5 activity is induced by growth factors, such as nerve growth factor (NGF)130 and BDNF,131 which increase p35 transcription via ERK-mediated activation of the transcription factor Egr1.130 Repeated activation of dopamine receptors by exposure to addictive drugs results in accumulation of the long-half-life transcription factor deltaFosB, a splice variant of FosB that increases the transcription of Cdk5.132 Induction of hippocampal deltaFosB by electroconvulsive treatments increases expression of hippocampal Cdk5 in rats.133 Cdk5 activity is primarily measured by assessing the phosphorylation of some of the many specific Cdk5 substrates, which include Ser-551 and Ser-553 of synapsin
