A mouse model for the learning and memory deficits associated with neurofibromatosis type I

Abstract

Neurofibromatosis type I (NF1) is one of the most commonly inherited neurological disorders in humans, affecting approximately one in 4,000 individuals1–3. NF1 results in a complex cluster of developmental and tumour syndromes that include benign neurofibromas, hyperpigmentation of melanocytes and hamartomas of the iris. Some NF1 patients may also show neurologic lesions, such as optic pathway gliomas, dural ectasia and aqueduct stenosis1–3. Importantly, learning disabilities occur in 30% to 45% of patients with NF1, even in the absence of any apparent neural pathology. The learning disabilities may include a depression in mean IQ scores, visuoperceptual problems and impairments in spatial cognitive abilities4–9. Spatial learning has been assessed with a variety of cognitive tasks and the most consistent spatial learning deficits have been observed with the Judgement of Line Orientation test4,7,10,11. It is important to note that some of these deficits could be secondary to developmental abnormalities1 and other neurological problems, such as poor motor coordination and attentional deficits9. Previous studies have suggested a role for neurofibromin in brain function. First, the expression of the Nf1 gene is largely restricted to neuronal tissues in the adult12,14. Second, this GTPase activating protein may act as a negative regulator of neurotrophin-mediated signalling15. Third, immunohistochemical studies suggest that activation of astrocytes may be common in the brain of NF1 patients13. Here, we show that the Nf1+/− mutation also affects learning and memory in mice. As in humans, the learning and memory deficits of the Nf1+/− mice are restricted to specific types of learning, they are not fully penetrant, they can be compensated for with extended training, and they do not involve deficits in simple associative learning.