Date of Award
Medical Doctor (MD)
Nonreceptor, proline-rich tyrosine kinase 2 (Pyk2) is a member of the
focal adhesion kinase (FAK) family. Of the three known isoforms, the
unspliced form of Pyk2 is most highly expressed in the CNS and has the
highest abundance in striatum, cortex, lateral septum, and
hippocampus(1, 2)(1, 2). Through regulation of NMDA receptor activity,
Pyk2 has been shown to play a crucial role in synaptic plasticity.
Given the high abundance of Pyk2 in the striatum and its known role in
synaptic plasticity, we hypothesized that disruption of Pyk2 function would
diminish the observed behavioral response to chronic cocaine. We
created a transgenic mouse line using the tetracycline inducible
transgene system. Quantitative real-time PCR was utilized to measure
mRNA levels and to characterize the mutant mice. In addition,
immunoprecipitation experiments were conducted to verify the presence
of mutant Pyk2 protein in the striatum and nucleus accumbens.
Disruption of behavioral sensitization in response to cocaine was
observed in the transgenic mice, while sensitization was preserved in
wild-type mice. There was no significant difference in phosphorylation of
NMDAR-NR2B. These findings, however, do not allow us to definitively
conclude that the presence of mutant Pyk2 diminishes the locomotor
effects of the cocaine mediated synaptic plasticity. Taken together, Pyk2
could be a potential target for pharmacologic therapy in drug addiction.
Edwards, Fayola, "Characterization Of Mutant Pyk2 And Cocaine Sensitization In Mice" (2012). Yale Medicine Thesis Digital Library. 1710.