Editors' ChoicePsychiatry

Focusing on Attention Deficit

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Science Translational Medicine  11 May 2011:
Vol. 3, Issue 82, pp. 82ec69
DOI: 10.1126/scitranslmed.3002576

Children often seem to have boundless energy, but when youthful activity crosses over to hyperactivity, it is time to think about attention deficit hyperactivity disorder (ADHD). ADHD is a common behavioral and cognitive condition affecting one in 20 children that can extend into adolescence and beyond and severely compromise one’s quality of life. New treatments for this debilitating disease are needed, but the underlying etiology of ADHD has not been elucidated. However, psychostimulants such as amphetamines or methylphenidate can attenuate symptoms. Now, Won et al. have discovered a new genetic aberration linked to ADHD and designed a related genetic mouse model that should aid in mechanistic studies and, eventually, therapeutic discovery efforts.

ADHD patients display the following characteristic symptoms: hyperactivity, inattention, and cognitive deficits (impaired learning and memory). The authors demonstrated that a single-nucleotide polymorphism (SNP) in the human GIT1 gene is associated with an adjusted 2.7-fold increase in the risk of ADHD in a population of 388 unrelated Korean children. GIT1 encodes G protein–coupled receptor kinase—interacting protein 1 (GIT1), a multifunctional signal-transduction protein that is important for neurite outgrowth, neuronal synapse formation, and glutamatergic synaptic receptor localization; the ADHD-associated SNP resulted in a 50% reduction of GIT1 protein expression as compared with the major allele, as shown in an in vitro assay. In order to explore further the association between GIT1 and ADHD, Won and colleagues developed a mouse model in which they mutated both copies of the homologous mouse gene, Git1, resulting in the elimination of GIT1 protein expression. The resulting mice displayed ADHD-like behavior, including impaired learning and memory and increased locomotor activity as compared with controls. The hyperactive phenotype waned with age, as ADHD does in human patients. Remarkably, when the mutant mice were treated with amphetamines or methylphenidate, they demonstrated a reversal of behavioral, cognitive, and electroencephalographic abnormalities. It is important to note that this phenotype was expressed only when both alleles of the mouse gene were mutated, and thus, this model does not fully reflect the human genotype.

Having established a new animal model of ADHD, the authors turned their attention to mechanistic studies. By immunoblotting whole-brain homogenates, they found reduced expression of intracellular signaling molecules related to GIT1, including rho guanine nucleotide exchange factors, Ras-related C3 botulinum toxin substrate 1, and p-21 activated kinase, as well as presynaptic inhibitory proteins. Electrophysiology studies revealed reduced frequency of inhibitory postsynaptic currents. Interestingly, amphetamines did not reverse these abnormalities, suggesting that the therapeutic effects of psychostimulants on ADHD are accomplished via different physiological pathways. Thus, the discovery of a potential role for GIT1 in human ADHD pathogenesis points to a new therapeutic target pathway for the discovery of drugs that are mechanistically distinct from those used in current practice.

H. Won et al., GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice. Nat. Med. 17, 566–572 (2011). [PubMed]

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