To control behaviors, the brain has developed the ability to learn and retain memory related to advantageous behaviors. While the entire brain is involved in this process, our research focuses on two particular instances, reward/motor based learning mediated by the basal ganglia and contextual or associative learning mediated by the hippocampus.   The phenomenon of synaptic plasticity is thought mediate learning, where existing synapses are altered in strength (functional plasticity) and new synapses form de novo (structural plasticity).   We strive to understand the biochemical signal transduction mechanisms that underlie these processes by identifying and characterizing novel protein phosphorylation and dephosphorylation events as well as protein-protein interactions.   This is done by conducting proteomic studies and in vitro experiments using purified protein kinases, protein phosphatases and substrates.   Once a novel phosphorylation event is detected we identify the site of phosphorylation on the substrate of interest using mass spectroscopy and physical biochemistry approaches.   We then generate phosphorylation state specific antibodies that allow us to monitor the phosphorylation events in intact brain tissue.   The biochemical function of the phosphorylation event, often identified from in vitro studies, is assessed in whole animals or brain slices using a neuropharmacological approach.   These studies are then translated into neurophysiological studies to assess the contribution of the signaling event to the excitability and responsiveness of neurons and synaptic plasticity.   We use a behavioral approach to evaluate the role of the involved signaling pathway upon animal behavior.   To facilitate these studies we have developed a number of techniques that allow us to modulate signaling pathways in the brains of mice using genetic approaches.   Inducible knockout and viral gene delivery are two examples.   Neurophysiological studies to assess the effect of loss of a protein kinase or substrate include the field recordings utilizing a multi-electrode array and whole cell patch-clamp recordings.   Effects of loss of signaling pathways upon neuronal morphology are also sometimes assessed.   Major projects in the lab include study of the role of the neuronal protein kinase Cdk5 and regulatory subunits of protein phosphatase 1 in drug abuse, stroke, learning, and synaptic plasticity.   We are also studying the relationship of energy metabolism to neurotransmission as mediated by the biomodulator, adenosine and the psychostimulant caffeine.   Our ongoing studies are applicable to aging and a number of neurological and neuropsychiatric disorders including drug abuse, schizophrenia, ADHD, Huntington's disease, epilepsy, PTSD, and Parkinson's disease.   Furthermore, we are conducting studies to identify proteins involved in the etiology of neuropsychiatric disorders such as Tourette syndrome and obsessive-compulsive disorders. By characterizing and manipulating the biochemical pathways underlying learning and addiction, we hope to identify novel targets for the development of therapeutic treatments for these disorders.

Recent Publications

Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA. Cyclin-dependent kinase 5 governs learnign and synaptic plasticity via control of NMDAR degradation. Nature Neuroscience. Advanced Online publication: 2007 May 27

Nguyen C, Nishi A, Kansy JW, Fernandez J, Hayashi K, Gillardon F, Hemmings HC Jr, Nairn AC, Bibb JA. Regulation of protein phosphatase inhibitor-1 by cyclin-dependent kinase 5. J Biol Chem. 2007 Mar 30

Taylor JR, Lynch WJ, Sanchez H, Olausson P, Nestler EJ, Bibb JA. Inhibition of Cdk5 in the nucleus accumbens enhances the locomotor-activating and incentive-motivational effects of cocaine. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4147-52. Epub 2007 Feb 23.

Sahin B, Galdi S, Hendrick J, Greene RW, Snyder GL, Bibb JA. Evaluation of neuronal phosphoproteins as effectors of caffeine and mediators of striatal adenosine A2A receptor signaling. Brain Res. 2007 Jan 19;1129(1):1-14.

Kansy JW, Katsovich L, McIver KS, Pick J, Zabriskie JB, Lombroso PJ, Leckman JF, Bibb JA. Identification of pyruvate kinase as an antigen associated with Tourette syndrome. J Neuroimmunol. 2006 Dec;181:165-76.

Hayashi K, Pan Y, Shu H, Ohshima T, Kansy JW, White CL 3rd, Tamminga CA, Sobel A, Curmi PA, Mikoshiba K, Bibb JA. Phosphorylation of the tubulin-binding protein, stathmin, by Cdk5 and MAP kinases in the brain. J Neurochem. 2006 Aug 21

Sahin B, Shu H, Fernandez J, El-Armouche A, Molkentin JD, Nairn AC, Bibb JA. Phosphorylation of protein phosphatase inhibitor-1 by protein kinase C. J Biol Chem. 2006 Aug 25;281(34):24322-35.

Bibb JA. Decoding dopamine signaling. Cell. 2005 Jul 29;122(2):153-5.

Benavides DR, Bibb JA. Role of Cdk5 in drug abuse and plasticity. Ann NY Acad Sci. 2004 Nov; 1025:335-44.

Kansy JW, Daubner SC, Nishi A, Sotogaku N, Lloyd MD, Nguyen C, Lu L, Haycock JW, Hope B, Fitzpatrick PF, Bibb JA. Identification of tyrosine hydroxylase as a physiological substrate of Cdk5. J Neurochemistry. 2004 Oct; 91 (2):374-84.

Sahin B, Kansy JW, Nairn AC, Spychala J, Ealick SE, Fienberg AA, Greene RW, and Bibb JA. Molecular characterization of recombinant mouse adenosine kinase and evaluation as a target for protein phosphorylation. European Journal of Biochemistry. 271, 1-9 (2004)