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

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.

► We show that attention deficits in Nf1 mutant mice result from a presynaptic defect in striatal dopamine homeostasis. ► We demonstrate that this dopaminergic defect can be quantified in the intact animal using [11C]-raclopride PET. ► We show that drug treatments that increase striatal dopamine levels correct both the behavioral and PET imaging deficits. ► In contrast, restoration of normal cAMP or Ras signaling does not correct the behavioral or the PET imaging deficits. ► These findings establish a robust preclinical model for the evaluation of promising agents for NF1-associated ADD.