Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2), encoding a transcriptional repressor, cause Rett syndrome and a variety of related neurodevelopmental disorders. The vast majority of mutations associated with human disease are loss-of-function mutations, but precisely what aspect of MeCP2 function is responsible for these phenotypes remains unknown. We overexpressed wild-type human protein in transgenic mice using a large genomic clone containing the entire human MECP2 locus. Detailed neurobehavioral and electrophysiological studies in transgenic line MeCP2(Tg1), which expresses MeCP2 at approximately 2-fold wild-type levels, demonstrated onset of phenotypes around 10 weeks of age. Surprisingly, these mice displayed enhanced motor and contextual learning and enhanced synaptic plasticity in the hippocampus. After 20 weeks of age, however, these mice developed seizures, became hypoactive and approximately 30% of them died by 1 year of age. These data demonstrate that MeCP2 levels must be tightly regulated in vivo, and that even mild overexpression of this protein is detrimental. Furthermore, these results support the possibility that duplications or gain-of-function mutations in MECP2 might underlie some cases of X-linked delayed-onset neurobehavioral disorders.

Recessive mutations in genes encoding voltage-gated Ca 2ϩ channel subunits alter high-voltage-activated (HVA) calcium currents, impair neurotransmitter release, and stimulate thalamic low-voltage-activated (LVA) currents that contribute to a cortical spike-wave epilepsy phenotype in mice. We now report thalamic LVA current elevations in a non-Ca 2ϩ channel mutant. EEG analysis of Coloboma (Cm/؉), an autosomal dominant mutant mouse lacking one copy of the gene for a synaptosomal-associated protein (SNAP25) that interacts with HVA channels, reveals abnormal spike-wave discharges (SWDs) in the behaving animal. We compared the biophysical properties of both LVA and HVA currents in Cm/؉ and wild-type thalamic neurons and observed a 54% increase in peak current density of LVA currents evoked at Ϫ50 mV from Ϫ110 mV in Cm/؉ before the developmental onset of seizures relative to control. The midpoint voltage for steady-state inactivation of LVA currents in Cm/؉ was shifted in a depolarized direction by 8 mV before epilepsy onset, and the mean time constant for decay of LVA Ca 2ϩ currents at Ϫ50 mV was also prolonged. No significant differences were found in recovery from inactivation of LVA currents or in HVA current densities and kinetics. Our data demonstrate that a non-Ca 2ϩ channel subunit gene mutation leads to potentiated thalamic LVA currents that precede the appearance of SWDs and that altered somatodendritic HVA currents are not required for abnormal thalamocortical oscillations. We suggest that presynaptic release defects shared by these mutants lead to postsynaptic LVA excitability increases in thalamic pacemaker neurons that favor rebound bursting and absence epilepsy.

It has been empirically demonstrated that humor can positively affect psychological and physical well-being, and that sense of humor is a major component of high-hope individuals. In the current study, the authors examined the relationship between humor and hopefulness, stress and hopefulness, as well as the moderating effect of humor on the stress-hopefulness relationship. Prior to and after viewing either a humorous or a neutral video, participants completed the Snyder State Hope Scale. Results indicated that there was a statistically significant increase in state hopefulness after exposure to a humorous video relative to a control group viewing a neutral video. In addition, a negative relationship was found between the severity of recently experienced stressors and state hopefulness, but little or no relationship existed between state hope and the number of recent stressors. The findings support the positive influence of humor on state hopefulness.