Attention-Deficit/Hyperactivity Phenotype in Mice Lacking the Cyclin-Dependent Kinase 5 Cofactor p35

Justin M Drerup; Kanehiro Hayashi; Huxing Cui; Gabriel L Mettlach; Michael A Long; Marian Marvin; Xiankai Sun; Matthew S Goldberg; Michael Lutter; James A Bibb

doi:10.1016/j.biopsych.2010.07.016

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Attention-Deficit/Hyperactivity Phenotype in Mice Lacking the Cyclin-Dependent Kinase 5 Cofactor p35

Journal article

Peer reviewed

Attention-Deficit/Hyperactivity Phenotype in Mice Lacking the Cyclin-Dependent Kinase 5 Cofactor p35

Justin M Drerup, Kanehiro Hayashi, Huxing Cui, Gabriel L Mettlach, Michael A Long, Marian Marvin, Xiankai Sun, Matthew S Goldberg, Michael Lutter and James A Bibb

Biological psychiatry (1969), Vol.68(12), pp.1163-1171

2010

DOI: 10.1016/j.biopsych.2010.07.016

PMCID: PMC2997929

PMID: 20832057

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) may result from delayed establishment of corticolimbic circuitry or perturbed dopamine (DA) neurotransmission. Despite the widespread use of stimulants to treat ADHD, little is known regarding their long-term effects on neurotransmitter levels and metabolism. Cyclin-dependent kinase 5 (Cdk5) regulates DA signaling through control of synthesis, postsynaptic responses, and vesicle release. Mice lacking the Cdk5-activating cofactor p35 are deficient in cortical lamination, suggesting altered motor/reward circuitry. We employed mice lacking p35 to study the effect of altered circuitry in vivo. Positron emission tomography measured glucose metabolism in the cerebral cortex using 2-deoxy-2-[ 18F] fluoro- d-glucose as the radiotracer. Retrograde dye tracing and tyrosine hydroxylase immunostains assessed the effect of p35 knockout on the medial prefrontal cortex (PFC), especially in relation to mesolimbic circuit formation. We defined the influence of Cdk5/p35 activity on catecholaminergic neurotransmission and motor activity via examination of locomotor responses to psychostimulants, monoamine neurotransmitter levels, and DA signal transduction. Here, we report that mice deficient in p35 display increased glucose uptake in the cerebral cortex, basal hyperactivity, and paradoxical decreased locomotion in response to chronic injection of cocaine or methylphenidate. Knockout mice also exhibited an increased susceptibility to changes in PFC neurotransmitter content after chronic methylphenidate exposure and altered basal DAergic activity in acute striatal and PFC slices. Our findings suggest that dysregulation of Cdk5/p35 activity during development may contribute to ADHD pathology, as indicated by the behavioral phenotype, improperly established mesolimbic circuitry, and aberrations in striatal and PFC catecholaminergic signaling in p35 knockout mice.

Dopamine

methylphenidate

p35

Cdk5

prefrontal cortex

Attention-deficit/hyperactivity disorder (ADHD)

Details

Title: Subtitle: Attention-Deficit/Hyperactivity Phenotype in Mice Lacking the Cyclin-Dependent Kinase 5 Cofactor p35
Creators: Justin M Drerup - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
Kanehiro Hayashi - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
Huxing Cui - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
Gabriel L Mettlach - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
Michael A Long - Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
Marian Marvin - Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas
Xiankai Sun - Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
Matthew S Goldberg - Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas
Michael Lutter - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
James A Bibb - Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
Resource Type: Journal article
Publication Details: Biological psychiatry (1969), Vol.68(12), pp.1163-1171
DOI: 10.1016/j.biopsych.2010.07.016
PMID: 20832057
PMCID: PMC2997929
NLM abbreviation: Biol Psychiatry
ISSN: 0006-3223
eISSN: 1873-2402
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100009670, name: National Alliance for Research on Schizophrenia and Depression; DOI: 10.13039/100000002, name: US National Institutes of Health, award: K08 MH084058-1A1, UL1RR024923, RL1 DK081182, RL1DK081185, MH79710, DA016672
Language: English
Date published: 2010
Academic Unit: Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
Record Identifier: 9984040317702771

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