Bridging the Gap Between Mouse Behavior and Human Cognition in Neurofibromatosis Type 1
نویسنده
چکیده
Understanding the etiology of cognitive deficits in genetic disorders holds great promise for advancing disease-specific treatments. The availability of animal models has allowed detailed examination of molecular pathways underlying the cognitive phenotype in numerous Mendelian disorders, increasing optimism for mechanism-based treatments. One such disorder is neurofibromatosis type 1 (NF1), an autosomal dominant condition associated with high rates of neurocognitive deficits, academic failure, attention deficit hyperactivity disorder, psychosocial maladjustment and motor coordination problems (Champion et al., 2014; Payne et al., 2013). Mutations in the NF1 gene result in decreased levels of neurofibromin; a negative regulator of the RAS signaling cascade. Ensuing RAS hyperactivation increases activity-dependent GABAergic neurotransmission and reduces synaptic plasticity, resulting in behavioral impairment (Shilyansky et al., 2010). Preclinical trials demonstrate that genetic and pharmacological interventions inhibiting RAS transforming activity can rescue these cellular abnormalities and reverse themurine behavioral phenotype, providing a rationale for human clinical trials (Li et al., 2005). Despite significant promise, early attempts at translating these preclinicalfindings in randomized controlled trials have unfortunately failed (Krab et al., 2008; van der Vaart et al., 2013). Translation of findings from bench to clinically relevant therapies is notoriously complex, and treatments for cognitive deficits in patients with NF1 appear to be no different. There are many reasons for this including lack of evidence for the appropriate treatment dose to inhibit RAS activity in the brain and, more importantly, minimal validation of the preclinical disease model in the human disease state. The relative contributions of aberrant RAS signaling, altered GABAergic neurotransmission and deficient synaptic plasticity to the NF1 cognitive phenotype in humans is also unknown.
منابع مشابه
Mouse models of neurofibromatosis type I: bridging the GAP.
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عنوان ژورنال:
دوره 2 شماره
صفحات -
تاریخ انتشار 2015