Abstract
Children with neurofibromatosis type 1 (NF1) frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice). In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below) suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening) under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg) administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at ameliorating NF1-associated cognitive/behavioral deficits.
Highlights
Neurofibromatosis-1 (NF1) is an autosomal dominant genetic disorder associated with the development of benign and malignant tumors [1]
We have shown that this dopaminergic deficiency in Nf1 OPG mice is presynaptic in nature and may be quantified by {11C}-raclopride positron emission tomography (PET) [6]
Since decreased alternations may reflect spatial working memory impairments, we evaluated this possibility by transforming alternation scores with reference to the number of arm entries made in each mouse to calculate the percentage of spontaneous alternations (Figure 2C)
Summary
Neurofibromatosis-1 (NF1) is an autosomal dominant genetic disorder associated with the development of benign and malignant tumors [1]. In an effort to provide insight into the molecular and cellular mechanisms underlying NF1-associated cognitive and behavioral dysfunctions, we have performed studies involving a strain of Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice). We demonstrated that Nf1 OPG mice have mild spatial learning and memory impairments, as well as significant nonselective and selective attention deficits that result from reduced striatal dopamine levels [5]. We have demonstrated that a nonselective, exploratory-based attention deficit in Nf1 OPG mice is corrected by methylphenidate (MPH) and L-Deprenyl, which is associated with the normalization of raclopride binding in vivo [6]. Results from our studies with Nf1 OPG mice are consistent with findings from a cohort of children with NF1 which showed that performance on tests of attention and learning were significantly improved following treatment with MPH [8]
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