title: Attention-deficit/hyperactivity phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Drerup
authors.forename: Kanehiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Huxing
authors.initials: H
authors.lastname: Cui
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Mettlach
authors.forename: Michael A
authors.initials: MA
authors.lastname: Long
authors.forename: Marian
authors.initials: M
authors.lastname: Marvin
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Michael
authors.initials: M
authors.lastname: Lutter
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000818:Animals; D001284:Atrophy / Q000235:genetics; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009434:Neural Pathways / Q000473:pathology; D010641:Phenotype; D010770:Phosphotransferases / Q000235:genetics*; D049268:Positron-Emission Tomography / Q000379:methods; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
chemical_list: D004298:Dopamine; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D019788:Fluorodeoxyglucose F18; D008774:Methylphenidate; D010770:Phosphotransferases; D018091:Receptors, AMPA; D012701:Serotonin; C492236:Cdk5r1 protein, mouse; C497929:Ppp1r1b protein, mouse