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 individuals. 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 stenosis. 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 abilities. 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 test. It is important to note that some of these deficits could be secondary to developmental abnormalities and other neurological problems, such as poor motor coordination and attentional deficits. 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 adult. Second, this GTPase activating protein may act as a negative regulator of neurotrophin-mediated signalling. Third, immunohistochemical studies suggest that activation of astrocytes may be common in the brain of NF1 patients. 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.

Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins

“…c-fos and egr-1 are well-known immediate early genes demonstrated to be up-regulated in the hippocampus and in other brain structures in a number of classical and instrumental conditioning paradigms in mammals, and the Nf1 gene has been proven to be required for spatial learning in mice (34) and for olfactory associative learning in flies (35). The HuB and GAP-43 genes have been implicated in spatial learning here.…”

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…Although anxiety is a common feature of FXS, Fmr1 KO mice display low anxiety-like behaviors [69]. Low scores on learning and memory tasks such as water maze spatial navigation, fear-conditioned freezing, novel object recognition, and touchscreen visual discrimination were seen in mice with mutations in genes including Nf1, En2, 16p11.2 deletion, and Plaur with decreased gamma-aminobutryic acid-ergic cortical interneurons [20,28,[70][71][72]. Further investigations of phenotypes in mice that have face validity and neuroanatomical construct validity to both diagnostic and associated symptoms of autism may prove particularly revealing.…”

Abnormal Long-Lasting Synaptic Plasticity and Cognition in Mice Lacking the Mental Retardation GenePak3

“…In syndromic form of MR, cognitive impairments are usually associated with other physical and neurological deficits. A considerable progress has been made in understanding syndromic MR, including the establishment of several animal models (Dutch-Belgium Fragile X Consortium, 1994;Silva et al, 1997;Costa et al, 2001;Bourtchuladze et al, 2003;Alarcon et al, 2004;Korzus et al, 2004). In contrast, nonsyndromic MR is characterized by reduced cognitive function without any other clinical features, thus providing the most direct approach to specifically study the neurobiology of cognition and pathogenesis of MR (Chelly and Mandel, 2001;Ramakers, 2002).…”