ORIGINAL COMMUNICATION Paired associate learning in children with neurofibromatosis type 1: implications for clinical trials Jonathan M. Payne • Belinda Barton • E. Arthur Shores • Kathryn N. North Received: 23 February 2012 / Revised: 11 July 2012 / Accepted: 12 July 2012 / Published online: 9 August 2012 Ó Springer-Verlag 2012 Abstract Studies investigating behavior in mice with a heterozygous null mutation of the NF1 gene (Nf1 ?/- ) have provided critical insights into the molecular and cellular mechanisms underlying cognitive impairments associ- ated with neurofibromatosis type 1 (NF1). Hyperactivation of the Ras-MAPK signaling cascade, which results in increased GABA-mediated inhibition and significantly reduced long-term potentiation, has been proposed as a core mechanism underlying Nf1 ?/- mice deficits in visuospatial learning and attention. This assertion has been reinforced by preclinical trials that reveal that these impairments can be rescued both at a cognitive and cellular level. We attempted to demonstrate a phenotypic parallel between Nf1 ?/- mice and children with NF1 using a well-validated measure of visuospatial learning. Children with NF1 (n = 71) and healthy controls (n = 29) were assessed on a computerized paired associate learning task. Interrelationships between visuospatial learning and other cognitive abilities that may influence performance, such as intelligence, attention and visuospatial function, were explored. Children with NF1 displayed significant impairments in visuospatial learning, with reduced initial retention and poorer learning across repeated trials. Importantly, we demonstrated that visuo- spatial learning was inferior in NF1 even after accounting for group differences in intelligence, sustained attention and visuospatial abilities. We have thus identified impaired visuospatial learning as a core phenotypic feature in chil- dren with NF1. These findings imply that hippocampal- based learning networks are dysfunctional in children with NF1 and provide validation for a primary outcome measure for clinical trials aiming to correct aberrant Ras signaling. Keywords Neurofibromatosis type 1 Á Visuospatial learning Á Ras-MAPK signaling cascade Á CANTAB Á Clinical trials Introduction With a prevalence of 1 in 3,500, neurofibromatosis type 1 (NF1) is one of the most common single gene disorders to affect the human nervous system [1]. Cognitive impairment is the most common complication of NF1 in childhood, with up to 80 % of children displaying a moderate-to- severe impairment in at least one area of cognitive function [2]. While intelligence is only mildly affected, studies consistently show specific cognitive impairments on mea- sures of attention, executive function, language and visual perception [2–4]. It is not clear whether children with NF1 experience impairments in hippocampal-based learning and recent memory [5]. Mice with a heterozygous null mutation of the Nf1 gene (Nf1 ?/- ) have provided an important experimental tool in J. M. Payne (&) Á K. N. North Institute for Neuroscience and Muscle Research, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145, Australia e-mail: jonathan.payne@health.nsw.gov.au J. M. Payne Á B. Barton Á K. N. North Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia B. Barton Children’s Hospital Education Research Institute, The Children’s Hospital at Westmead, Westmead, Sydney, Australia E. A. Shores Department of Psychology, Macquarie University, Sydney, Australia 123 J Neurol (2013) 260:214–220 DOI 10.1007/s00415-012-6620-5