Elsevier

Biological Psychiatry

Volume 68, Issue 12, 15 December 2010, Pages 1163-1171
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2010.07.016Get rights and content

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.

Section snippets

Positron Emission Tomography/Computed Tomography Imaging

Small animal positron emission tomography (PET)/computed tomography (CT) imaging studies were performed using a Siemens Inveon Multimodality PET/CT system (Siemens Medical Solutions, Inc., Knoxville, Tennessee). Animals were anesthetized using 2% isoflurane for the duration of the imaging. The micro-computed tomography imaging was acquired at 80 kV and 500 mA with a focal spot of 58 μm. The total rotation of the gantry was 360° with 360 rotation steps obtained at an exposure time of 175

p35 KO Results in Increased Rate of Cortical Glucose Uptake

Positron emission tomography provides a noninvasive platform for the measurement of regional metabolism or neurotransmission in vivo. To assess the overall effect of p35 KO on brain function, p35−/− and wild-type (WT) littermates (10–12 weeks old) were injected with FDG and imaged by PET. A 60-minute dynamic PET scan revealed a significantly greater rate of glucose uptake in the cerebral cortex of p35−/− mice (Figure 1A,B). Linear regression analysis of the best-fit line (R2 = .96 for WT, .97

Discussion

Improper or delayed establishment of the mesocorticolimbic pathway may contribute to psychiatric disease, including ADHD (4, 6, 7, 8). Indeed, the PFC is highly implicated in attentional and hyperactivity disorders, as therapeutic doses of MPH selectively modify neurotransmission in this area (15). Here, we have shown that p35 KO compromised layer specificity of mPFC afferents projecting to the NAc. Additionally, an increase in PFC innervation by TH-positive fibers, increased basal PKA

References (66)

  • B. Sahin et al.

    Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C

    Eur J Pharmacol

    (2008)
  • L.C. Schmued et al.

    Fluoro-Gold: A fluorescent retrograde axonal tracer with numerous unique properties

    Brain Res

    (1986)
  • K.W. Roche et al.

    Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit

    Neuron

    (1996)
  • D. Law-Tho et al.

    Dopamine modulation of synaptic transmission in rat prefrontal cortex: An in vitro electrophysiological study

    Neurosci Res

    (1994)
  • P.W. Kalivas et al.

    Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization motor activity

    Brain Res Rev

    (1991)
  • K.E. Banks et al.

    Possible involvement of medial prefrontal cortex in amphetamine-induced sensitization of mesolimbic dopamine function

    Eur J Pharmacol

    (1995)
  • M. Ernst et al.

    Reduced brain metabolism in hyperactive girls

    J Am Acad Child Adolesc Psychiatry

    (1994)
  • Diagnostic and Statistical Manual of Mental Disorders

    (2000)
  • A.J. Zametkin et al.

    Cerebral glucose metabolism in adults with hyperactivity of childhood onset

    N Engl J Med

    (1990)
  • J.N. Giedd et al.

    Quantitative morphology of the corpus callosum in attention deficit hyperactivity disorder

    Am J Psychiatry

    (1994)
  • D.G. Amen et al.

    High-resolution brain SPECT imaging in ADHD

    Ann Clin Psychiatry

    (1997)
  • F.X. Castellanos et al.

    Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder

    JAMA

    (2002)
  • A. Qiu et al.

    Basal ganglia volume and shape in children with attention deficit hyperactivity disorder

    Am J Psychiatry

    (2009)
  • P. Shaw et al.

    Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation

    Proc Natl Acad Sci U S A

    (2007)
  • Y.S. Ding et al.

    Carbon-11-d-threo-methylphenidate binding to dopamine transporter in baboon brain

    J Nucl Med

    (1995)
  • S. Vijayraghavan et al.

    Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory

    Nat Neurosci

    (2007)
  • S. Granon et al.

    Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex

    J Neurosci

    (2000)
  • Y. Chudasama et al.

    Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex

    Neuropsychopharmacology

    (2004)
  • T.P. Zahn et al.

    Autonomic and behavioral effects of dextroamphetamine and placebo in normal and hyperactive prepubertal boys

    J Abnorm Child Psychol

    (1980)
  • M.I. Seaman et al.

    Tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4)

    Am J Med Genet

    (1999)
  • J.T. McCracken et al.

    Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD)

    Mol Psychiatry

    (2000)
  • V. Kustanovich et al.

    Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association with DRD4 and DRD5

    Mol Psychiatry

    (2004)
  • B. Kim et al.

    Association between dopamine D4 receptor gene polymorphism and scores on a continuous performance test in Korean children with attention deficit hyperactivity disorder

    Psychiatry Investig

    (2009)
  • Cited by (48)

    • Haloperidol and methylphenidate alter motor behavior and responses to conditioned fear of Carioca Low-conditioned Freezing rats

      2021, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      These animals also show loss of descending medial prefrontal cortex (mPFC) outputs to the nucleus accumbens and an increase of dopaminergic afferents projecting from the ventral tegmental area to the mPFC. Consequently, methylphenidate leads to an increased susceptibility to changes in PFC neurotransmitter content and to an effect on the locomotor activity by restoring the dopamine content in the striatum (Drerup et al., 2010; Krapacher et al., 2010). Although DAT constitutes the main target of methylphenidate and is linked to the effects of this drug on hyperactivity and reward mechanisms (Fagan et al., 2021; Giros et al., 1996; Kume et al., 2005; Pizzo et al., 2013; Wisor et al., 2001), other components of the dopamine pathway are also involved.

    • Lack of Cdk5 activity is involved on Dopamine Transporter expression and function: Evidences from an animal model of Attention-Deficit Hyperactivity Disorder

      2021, Experimental Neurology
      Citation Excerpt :

      ADHD is one of the most common psychiatric conditions affecting both children and adults worldwide (Sayal et al., 2018). We have previously shown that the mutant mouse lacking p35 protein presents key hallmarks that resemble those of ADHD, thus supporting its validity as a genetically modified animal model useful for studying the disorder (de la Peña et al., 2017; Drerup et al., 2010; Krapacher et al., 2010). Besides, we also shown that p35KO presents increased TH protein levels, increased DA content and decreased DA degradation which result in a low neurotransmitter turnover (Krapacher et al., 2010).

    • Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT <inf>1A</inf> receptor via phosphorylation

      2019, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      In adult brains, Cdk5–p35 modulates the synaptic activity at both presynaptic and postsynaptic termini by phosphorylating a number of synaptic proteins, such as dynamin, amphyphysin, calcium channel proteins, NR2B, and PSD-95 [14–17]. Studies on mice with a conditional Cdk5 knockout, whose neuronal positioning is normal, point to an association with neuropsychiatric disorders [18]. Nevertheless, it is not fully understood yet how Cdk5 regulates these brain development processes and particularly how it is involved in psychiatric problems.

    View all citing articles on Scopus

    Authors JMD and KH contributed equally to this work.

    View full text