Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1.

Children with neurodevelopmental disorders are at increased risk for sleep issues, which affect quality of life, cognitive function, and behavior. To determine the prevalence of sleep problems in children with the common neurodevelopmental disorder neurofibromatosis type 1, a cross-sectional study was performed on 129 affected subjects and 89 unaffected siblings, age 2 to 17 years, using the Sleep Disturbance Scale for Children questionnaire. Children with neurofibromatosis type 1 were significantly more likely to have disturbances in initiating and maintaining sleep, arousal, sleep-wake transition, and hyperhidrosis, but not problems with abnormal sleep breathing, or excessive somnolence. Although the overall sleep scores were higher in children with neurofibromatosis type 1, this was not related to a coexisting attention deficit disorder, cognitive impairment, or stimulant medication use. Collectively, these results demonstrate that children with neurofibromatosis type 1 are more likely to have sleep disturbances, and support the use of appropriate interventions for this at-risk population.

A physiological role for amyloid-beta protein:enhancement of learning and memory.

Amyloid-beta protein (Abeta) is well recognized as having a significant role in the pathogenesis of Alzheimer's disease (AD). The reason for the presence of Abeta and its physiological role in non-disease states is not clear. In these studies, low doses of Abeta enhanced memory retention in two memory tasks and enhanced acetylecholine production in the hippocampus in vivo. We then tested whether endogenous Abeta has a role in learning and memory in young, cognitively intact mice by blocking endogenous Abeta in healthy 2-month-old CD-1 mice. Blocking Abeta with antibody to Abeta or DFFVG (which blocks Abeta binding) or decreasing Abeta expression with antisense directed at the Abeta precursor, AbetaPP, all resulted in impaired learning in T-maze foot-shock avoidance. Finally, Abeta 1-42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to Abeta inhibited hippocampal LTP. In conclusion, these results indicate that in normal healthy young animals the presence of Abeta is important for learning and memory.

Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex.

Mice with inactivation of the Tuberous sclerosis complex-1 (Tsc1) gene in glia (Tsc1 GFAP CKO mice) have deficient astrocyte glutamate transporters and develop seizures, suggesting that abnormal glutamate homeostasis contributes to neurological abnormalities in these mice. We examined the hypothesis that Tsc1 GFAP CKO mice have elevated extracellular brain glutamate levels that may cause neuronal death, abnormal glutamatergic synaptic function, and associated impairments in behavioral learning. In vivo microdialysis documented elevated glutamate levels in hippocampi of Tsc1 GFAP CKO mice and several cell death assays demonstrated neuronal death in hippocampus and neocortex. Impairment of long-term potentiation (LTP) with tetanic stimulation was observed in hippocampal slices from Tsc1 GFAP CKO mice and was reversed by low concentrations of NMDA antagonist, indicating that excessive synaptic glutamate directly inhibited LTP. Finally, Tsc1 GFAP CKO mice exhibited deficits in two hippocampal-dependent learning paradigms. These results suggest that abnormal glutamate homeostasis predisposes to excitotoxic cell death, impaired synaptic plasticity and learning deficits in Tsc1 GFAP CKO mice.

Ghrelin controls hippocampal spine synapse density and memory performance.

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model.

Excessive astrocytosis in cortical tubers in tuberous sclerosis complex (TSC) suggests that astrocytes may be important for epileptogenesis in TSC. We previously demonstrated that astrocyte-specific Tsc1 gene inactivation in mice (Tsc1 cKO mice) results in progressive epilepsy. Here, we report that glutamate transporter expression and function is impaired in Tsc1 cKO astrocytes. Tsc1 cKO mice exhibit decreased GLT-1 and GLAST protein expression. Electrophysiological assays demonstrate a functional decrease in glutamate transport currents of Tsc1 cKO astrocytes in hippocampal slices and astrocyte cultures. These findings suggest that Tsc1 inactivation in astrocytes causes dysfunctional glutamate homeostasis, leading to seizure development in TSC.