Latrophilin-3 and ADHD: A new potential mechanism

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) affects 5.4 million children at a cost >$72 billion/year, yet its etiology is poorly understood. A new gene for an orphan receptor has been identified that conveys high risk for ADHD: Latrophilin-3 (LPHN3). We have a new Lphn3 knock-out (KO) rat. This rat shows hyperactivity and hyper-reactivity. But ADHD also affects attention and impulse control. Objective-1 will test Lphn3 KO rats for attention and inhibitory control. ADHD is treated with stimulants, which increase attention and reduce distractibility and activity. Objective-2 is to test the effects of ADHD medications in Lphn3 KO rats. Effective ADHD medications increase dopamine and norepinephrine signaling (and some increase 5HT) by acting on monoamine reuptake and release processes or receptors. Objective-3 is to determine the effects of Lphn3 disruption on monoamines, transporters, and receptors. The overall purpose is to identify the contribution of Lphn3 to the behavioral and neurochemical phenotype of ADHD. The proposed experiments will generate essential data for how Lphn3 contributes to each of the symptoms and neurochemical changes associated with ADHD. Lphn3 could become a novel target for development of drugs that modulate Lphn3 function or its binding partner (Flrt3) to alleviate the underlying deficit in ADHD. As such this represents innovative research on a cause of ADHD. We are the only group with the Lphn3 KO rat and pilot phenotypic data. Therefore, we are uniquely position to pursue this model. Specific Aim-1 will determine the ADHD-like phenotype of Lphn3 KO rats. The role of Lphn3 loss of function in extended locomotor activity, sensorimotor gating, cognitive flexibility/attention (set shifting), attention/flexibility (continuous performance test), working memory, and response to ADHD medications will be assessed. The data will demonstrate the range and severity of ADHD phenotype. Specific Aim-2 will elucidate the neurochemical changes in Lphn3 KO rats. Exp-2a: KO and WT rats will be compared by immunohistochemistry for changes in monoamines implicated in ADHD (dopamine (by tyrosine hydroxylase), 5HT, and dopamine beta hydroxylase (for NE), and as controls GAD67 (for GABA) and NMDA-NR1 (for glutamate). Stains for each transporter will be performed. Because the dopamine D4 and 5HT2B receptors have been implicated in ADHD they will also be assessed. Exp-2b: Once histological regions of change are identified, other animals will have these regions analyzed by Western blot. Exp-2c: Once Westerns from Aim-2b identify significant changes, this will be used to guide which markers will be analyzed in Aim-2c in animals after behavioral testing; then correlations between neurochemical and behavioral data will be performed. In addition, RT-PCR for Flrt3 will be performed to determine it is altered by the Lphn3 mutation. These experiments will materially advance the field of ADHD research.