Cognition is dependent upon the proper formation of neural circuits and the adaptations of those circuits in response to experience. The cellular and molecular mechanisms underlying declarative learning and memory constitute a predominant area in basic neurobiological research and are of considerable clinical relevance. Dysregulation of the biochemical mechanisms underlying cognition likely contributes to neurodevelopmental and neurodegenerative disorders including autism, Alzheimer's, mental retardation, schizophrenia, and attention deficit and hyperactivity disorder. We have focused on synaptic signal transduction mechanisms involving the neuronal protein kinase Cdk5, with the goal of determining its role in learning and memory. We developed an innovative transgenic approach that allowed the induction of knockout of the neuronal protein throughout the brain of adult mice. This led to the discovery that the neuronal protein kinase Cdk5 governs synaptic plasticity, learning, and memory. We found that this was due to changes in the levels and surface expression of the NR2B subunit of the NMDA receptor. Here we propose to characterize the interactions between Cdk5 and NR2B, evaluate the role of Cdk5-NR2B interactions in synaptic plasticity, and assess the role of Cdk5-NR2B interaction in learning, and memory. The proposed studies are based on our preliminary findings that Cdk5 phosphorylates NR2B at a novel site and this phosphorylation controls the translocation of the receptor to the synaptic cell surface. We will characterize the regulation of this important site with regard to phosphorylation/dephosphorylation and define its physiological function. We hypothesize that the phosphorylation state of NR2B is dynamically regulated during learning and essential for consolidation of memory in the hippocampus. Furthermore, we show that are developing small drug-like interfering peptides based that disrupt Cdk5-NR2B interactions in vitro and in vivo. We will use this selective targeting approach to manipulate Cdk5-NR2B interactions and bidirectionally control the phosphorylation state and surface levels of NR2B. This will allow us to modulate synaptic plasticity, learning and memory in the hippocampus. Thus by combining advanced transgenic, biochemical, neurophysiological and behavioral approaches, we will define an important new mechanism that mediates cognition and demonstrate it as a target for the possible development of innovate disruption strategies to treat cognitive disorders.

Public Health Relevance

Unlike many other diseases, the high levels of morbidity and health care burden of neurodevelopmental and neurodegenerative disorders has not been reduced by modern advances in medicine. Many neuropsychiatric and neurological illnesses such as autism, Alzheimer's, mental retardation, schizophrenia, and attention deficit and hyperactivity disorder may involve the dysregulation of the cellular and molecular mechanisms that mediate cognition. The goal of this research is to identify and understand novel biochemical mechanisms that mediate cognition and develop reagents that will improve learning and memory, and lead to innovative disruption strategies for mental illness and neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH083711-01A1
Application #
7866207
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
2010-03-12
Project End
2014-12-31
Budget Start
2010-03-12
Budget End
2010-12-31
Support Year
1
Fiscal Year
2010
Total Cost
$396,250
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Hernandez, Adan; Tan, Chunfeng; Plattner, Florian et al. (2018) Exposure to mild blast forces induces neuropathological effects, neurophysiological deficits and biochemical changes. Mol Brain 11:64
Pozo, Karine; Bibb, James A (2016) The Emerging Role of Cdk5 in Cancer. Trends Cancer 2:606-618
Hernandez, Adan; Tan, Chunfeng; Mettlach, Gabriel et al. (2016) Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum. Sci Rep 6:29812
Bjorness, Theresa E; Dale, Nicholas; Mettlach, Gabriel et al. (2016) An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep. J Neurosci 36:3709-21
Yousuf, Mohammad A; Tan, Chunfeng; Torres-Altoro, Melissa I et al. (2016) Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury. J Neurochem 138:317-27
Tassin, Tara C; Benavides, David R; Plattner, Florian et al. (2015) Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain. J Biol Chem 290:16319-29
Fan, Gaofeng; Aleem, Saadat; Yang, Ming et al. (2015) Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase. J Biol Chem 290:15934-47
Plattner, Florian; Hayashi, Kanehiro; Hernández, Adan et al. (2015) The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci 18:1094-100
Pozo, Karine; Hillmann, Antje; Augustyn, Alexander et al. (2015) Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis. Oncotarget 6:12080-93
Mettlach, Gabriel; Polo-Parada, Luis; Peca, Lauren et al. (2014) Enhancement of neuromuscular dynamics and strength behavior using extremely low magnitude mechanical signals in mice. J Biomech 47:162-7

Showing the most recent 10 out of 23 publications