PET imaging for attention deficit preclinical drug testing in neurofibromatosis-1 mice

Abstract

Attention system abnormalities represent a significant barrier to scholastic achievement in children with neurofibromatosis-1 (NF1). Using a novel mouse model of NF1-associated attention deficit (ADD), we demonstrate a presynaptic defect in striatal dopaminergic homeostasis and leverage this finding to apply [11C]-raclopride positron-emission tomography (PET) in the intact animal. While methylphenidate and L-Deprenyl correct both striatal dopamine levels on PET imaging and defective attention system function in Nf1 mutant mice, pharmacologic agents that target de-regulated cyclic AMP and RAS signaling in these mice do not. These studies establish a robust preclinical model to evaluate promising agents for NF1-associated ADD.

CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies

“…Using novel Nf1 genetically engineered mice, he observed that agents which restore striatal dopamine levels in the brain can reverse the behavioral abnormalities in these mice [Brown et al, 2010]. He further showed that raclopride positron emission tomography imaging could be used to reveal dopamine defects in Nf1 mutant mice [Brown et al, 2011]. …”

The Learning Disabilities Network (LeaDNet): Using neurofibromatosis type 1 (NF1) as a paradigm for translational research

“…In addition to functioning as a negative RAS regulator, studies in Drosophila and mouse homozygous cells indicate that neurofibromin is also a positive regulator of the cAMP/PKA pathway [Dasgupta et al, 2003; Brown et al, 2011, 2012]. In flies, cAMP signaling is critical for learning.…”

“…Similar to children with NF1, the attention system dysfunction in these mice is reversed by treatment with methylphenidate (MPH) suggesting a defect in brain catecholamine homeostasis. Using several methods, including positron emission tomography (PET), these studies demonstrated that the attention system abnormalities in Nf1 OPG mice are the consequence of reduced dopamine (DA) levels in the striatum, which is normalized following either MPH or L -dopa administration [Brown et al, 2011]. Interestingly, previous studies demonstrated that the attention deficits observed in Nf1 +/− mice could be reversed with a drug (lovastatin) that reversesþthe increased Ras signaling and abnormally high GABA release deficits described in these mice.…”

“…These results with the mutant mice provide an incentive for pursuing comprehensive clinical trials of stimulant medication in children with NF1. The availability of preclinical Nf1 mouse models with attention system deficits, which can be rapidly assessed behaviorally and neurochemically (PET imaging) [Brown et al, 2010a, 2011], provide new opportunities for understanding the genomic and environmental variables that could affect the clinical impact of MPH treatments.…”

Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: a study protocol for a randomised placebo-controlled crossover trial

“…These behavioural deficits have been linked to a presynaptic DA defect in the striatum36 and hippocampus 35. In vivo experiments using positron emission tomography imaging with 11 C-raclopride have extended these research findings demonstrating increased striatal binding, consistent with abnormally low DA levels 34. Treatment with methylphenidate (MPH), a stimulant medication that increases extracellular DA availability by inhibiting its reuptake by the DA transporter, corrected mice behavioural abnormalities and restored the DA levels in the striatum and hippocampus 34–36.…”