A MOUSE MODEL FOR THE LEARNING AND MEMORY DEFICITS ASSOCIATED WITH NEUROFIBROMATOSIS TYPE-I

Neurofibromatosis type I (NF1) is one of the most commonly inherited n eurological disorders in humans, affecting approximately one in 4,000 individuals(1-3). NF1 results in a complex cluster of developmental an d tumour syndromes that include benign neurofibromas, hyperpigmentatio n of melanocytes and hamartomas of the iris. Some NF1 patients may als o show neurologic lesions, such as optic pathway gliomas, dural ectasi a and aqueduct stenosis(1-3). Importantly, learning disabilities occur in 30% to 45% of patients with NF1, even in the absence of any appare nt neural pathology. The learning disabilities may include a depressio n in mean IQ scores, visuoperceptual problems and impairments in spati al cognitive abilities(4-9). Spatial learning has been assessed with a variety of cognitive tasks and the most consistent spatial learning d eficits have been observed with the Judgement of Line Orientation test (4,7,10,11). It is important to note that some of these deficits could be secondary to developmental abnormalities(1) and other neurological problems, such as poor motor coordination and attentional deficits(9) . Previous studies have suggested a role for neurofibromin in brain fu nction. First, the expression of the Nf1 gene is largely restricted to neuronal tissues in the adult(12-14). Second, this GTPase activating protein may act as a negative regulator of neurotrophin-mediated signa lling(15). Third, immunohistochemical studies suggest that activation of astrocytes may be common in the brain of NF1 patients(13). Here, we show that the Nf1(+/-) mutation also affects learning and memory in m ice. As in humans, the learning and memory deficits of the Nf1(+/-) mi ce are restricted to specific types of learning, they are not fully pe netrant, they can be compensated for with extended training, and they do not involve deficits in simple associative learning.