Cognitive Research

Deficits in intellectual function are comorbid with many mental illnesses and neurological disorders. Mental retardation, autism, attention deficit disorder, schizophrenia, and depression all have cognitive components, as do Alzheimer ’s, Parkinson’s, Huntington’s, and other neurodegenerative diseases. Furthermore cognitive decline and memory impairment accompanies age-related changes in the brain and can indicate the onset of dementia. Cognitive enhancement is viewed as a strategy to treat these diseases, or to slow the effects of aging on brain function.

Cognition is mediated by changes in the biochemical constituency of synaptic machinery. We are characterizing signaling component of this machinery that underlie memory consolidation. We are particularly interested in the coordinated regulation of ionotropic glutamate receptors such as NMDA receptors and their synergy with cAMP signaling during synaptic remodeling and the consolidation of memory. The use of conditional knockout mice, viral gene transfer, neurophysiology and behavioral studies, and the development of small drug like peptides that interfere with protein interactions is providing insight into the processes underlying learning and new approaches for the development of selective and specific therapeutics to improve cognition.

Review the following publications to learn more about our mood disorder research:

  • Hernandez A, Tan C, Mettlach G, Pozo K, Plattner F, Bibb JA. Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum. Sci Rep. 2016 Jul 22; 6:29812.

  • Plattner F, Hayashi K, Hernández A, Benavides DR, Tassin TC, Tan C, Day J, Fina MW, Yuen EY, Yan Z, Goldberg MS, Nairn AC, Greengard P, Nestler EJ, Taussig R, Nishi A, Houslay MD, Bibb JA. The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci. 2015 Aug; 18(8):1094-100

  • Tassin TC, Benavides DR, Plattner F, Nishi A, Bibb JA. Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain. J Biol Chem. 2015 Jun 26; 290 (26):16319-29.

  • Plattner F, Hernández A, Kistler TM, Pozo K, Zhong P, Yuen EY, Tan C, Hawasli AH, Cooke SF, Nishi A, Guo A, Wiederhold T, Yan Z, Bibb JA. Memory enhancement by targeting Cdk5 regulation of NR2BNeuron. 2014 Mar 5; 81(5): 1070-83.

  • Plattner, F., Hernandéz, A., Kistler, T. M., Pozo, K., Zhong, P., Yuen, E., Hawasli, A., Cooke, S., Tan, C., Guo, A., Weiderhold, T., Yan, Z., Bibb, J.A. (2014) Memory enhancement by targeting Cdk5 regulation of NR2B, in press, Neuron

  •  Drerup, J.M., Hayashi, K, Cui, H., Mettlach, G.L., Long, M.A., Marvin, M., Sun, X., Goldberg, M.S., Lutter, M. Bibb, J.A. (2010) Attention-Deficit/Hyperactivity-like phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35, Jour. of Biol. Psych. 68:1163-71 Dec. 15, 2010 issue cover photo.

  • Bibb, J.A., Mayford, M.R., Tsien, J.Z., Alberini, C.M. (2010) Cognition Enhancement Strategies, J. Neurosci. 30:14987-92.

  • Hawasli, A., Koovakkattu, D., Hayashi, K., Powell, C.M., Sinton, C., Bibb, J.A., and Cooper, D,.C. (2009) Regulation of hippocampal and behavioral excitability by cyclin-dependent kinase 5,  PLOSOne, 4:e5808.
  • Hawasli, A.H. and Bibb, J.A. (2007) Alternative roles for Cdk5 in learning and synaptic plasticity. Journal of Biotechnology, 2:941-948.

  • Hawasli, A.H., Benavides, D.R., Nguyen, C., Kansy, J.W., Chambon, P, Greengard, P., Powell, C.M., Cooper, D.C., and Bibb, J.A. (2007) Cdk5 governs learning, memory and synaptic plasticity via control of NMDA receptor degradation. Nature Neuroscience10:880-886.

  • Nguyen, C., Kansy, J. W., Fernandez, J., Gillardon, F., Allen, P.B., Hemmings, H.C., Jr., Nairn, A.C., and Bibb, J.A. (2007) Regulation of protein phosphatase inhibitor-1 by Cyclin-dependent kinase 5. J. Biol. Chem. 282:16511-16520.

  • Sahin, B., Shu, H., Fernandez, J., Nairn, A.C., Molkentin, J.D., and Bibb, J.A. (2006) Dual phosphorylation of inhibitor-1 by PKC and Cdk5 regulates its conversion of an inhibitor of PP-1 by PKA in the striatum. J. Biol. Chem. 281: 24322-24335.

  • Wei, F.-Y., Tomizawa, K., Ohshima, T., Asada, A., Nguyen, C., Bibb, J.A., Ishiguro, K., Saito, T., Kulkarni, A.B., Pant H.C., Mikoshiba, K., Matsui, H., and S. Hisanaga (2005) Control of Cdk5 activity by glutamatergic regulation of p35 stability. J. Neurochem.93: 502-512.

  • Ohshima, T., Ogura H., Tomizawa, K., Hayashi, K., Saito, T., Kamei, H., Bibb, J.A., Hisanaga, S., Matsui, H. and K. Mikoshiba (2005) Defective learning and memory in p35-deficient mice. J. Neurochem. 94: 917-925.

Depression Research

Depression is a complex mental disorder with psychological symptoms that include anhedonia, hopelessness, change of appetite and sleep, loss of energy, and deterioration of cognitive functions. The molecular basis of depression is unknown and there is great need for more effective therapies. Patients with major depression display abnormal metabolic activity and anatomy within specific brain regions, including the basal ganglia, frontal cortex, and thalamus suggesting dysfunction of cortical-striatal and cortical-limbic reward pathways. Depression remains a pervasive neuropsychiatric disorder linked to significant morbidity and mortality.

Dopaminergic projections from the midbrain to limbic regions regulate reward, motivation, and decision-making. The symptoms of anhedonia and loss of motivation suggest dysfunction in this circuitry, and depression may be treated effectively by agents that modulate dopaminergic activity. These observations support the hypothesis that dysregulation of dopaminergic neurotransmission may serve as an important cause of depression. Aberrant PKA signaling has been implicated in mental illnesses including schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. Many therapeutic agents targeting these conditions act on monoamine receptors that regulate the cAMP/PKA cascade. We are studying the regulation of the G protein-coupled receptor/adenylate kinase/cAMP/PKA/phosphodiesterase signaling and characterizing novel mechanisms that may serve as therapeutic targets for drug discovery.

Review the following publications to learn more about our mood disorder research:

  • Kuroiwa, M., Snyder, G.L., Shuto, T., Fukuda, A., Yanagawa, Y., Bibb, J.A., Nairn, A.C., Greengard, P., and Nishi, A. (2011) A PDE4 inhibitor rolipram enhances dopamine D1 receptor/PKA/DARPP-32 signaling in cortical neurons, in press, Neuropsychopharmacology 219:1065-79.

  • Drerup, J.M., Hayashi, K, Cui, H., Mettlach, G.L., Long, M.A., Marvin, M., Sun, X., Goldberg, M.S., Lutter, M. Bibb, J.A. (2010) Attention-Deficit/Hyperactivity-like phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35, Jour. of Biol. Psych. 68:1163-71 Dec. 15, 2010 issue cover photo.

  • Kansy, J.W., Katsovich, L., McIver, K., Pick, J., Leckman, J.F., Lombroso, P.J., Zabriskie, J.B., and Bibb, J.A. (2006) Identification of pyruvate kinase as an antigen associated with Tourette syndrome. J. Nueruoimmunology181: 165-176.

  • Georgescu, D., Sears, R.M., Hommel, J.D., Barrot, M., Marsh, D.J., Bibb, J.A., Maratos-Flier, E., Nestler, E.J. and DiLeone, R.J. (2005) The neuropeptide MCH controls feeding behavior via a novel hypothalamic-limbic circuit. J. Neurosci.25: 2933-2940.

  • Nishi, A., Bibb, J.A., Higashi, H., Nairn, A.C. and Greengard, P. (2000) Amplification of dopaminergic signaling by a novel positive feedback loop. Proc. Natl. Acad. Sci. USA 97: 12840-12845.

  • 27. Mani, S.K., Fienberg, A.A., O’Callaghan, J.P., Snyder, G.L., Allen, P.B., Mitchell, A.J., Bibb, J.A., Greengard, P., and O’Malley, B.W. (2000) The neuronal phosphoprotein DARPP-32 is required for dopamine and progesterone-facilitated sexual behavior in female rodents. Science 287:1053-6.
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