Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice.

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

Effect of the postictal state on visual-spatial memory in immature rats.

Postictal cognitive impairment following seizures can last from minutes to days and be disabling to the patient. The purpose of this study was to compare the behavioral features of seizures with postictal memory impairment in young seizure-naive rats and rats with a prior history of status epilepticus (SE) and examine the relationship between postictal EEG changes and cognitive recovery. Following training in the water maze to asymptote levels of learning, rats with a prior history of SE and seizure-naive rats had flurothyl-induced generalized seizures and time to recovery to baseline was then measured. Following generalized seizures rats had impaired performance in the water maze with the duration of the cognitive deficits exceeding the length of the seizure. There was not a close relationship between duration of cognitive impairment and either latency to onset of seizure or duration. The animal's neurological status was a factor in the duration of cognitive impairment following seizures; while there were no differences between SE and seizure-naive rats in latency to seizure onset or duration of the seizures, animals with a prior history of SE had a longer period of impairment following a seizure than animals without such a history. Postictal cognitive impairment was associated with changes in theta activity in animals with a prior history of SEs but not in seizure-naive animals. Caffeine, when administered following the seizure, reduced postictal cognitive impairment in a dose-dependent manner. This study demonstrates that duration of postictal cognitive impairment is not directly related to duration of the seizure. The neurological status of the animal is a determining factor in duration of postictal impairment.

Detrimental effects of the ketogenic diet on cognitive function in rats.

The ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that is widely used to treat epilepsy in children. Although the KD has been shown to be efficacious in the treatment of childhood epilepsy, the long-term effects of the KD on brain development are not clear. The objective of this study was to examine the long-term effects of the KD on visual-spatial memory, activity level, and emotionality in immature rats after status epilepticus (SE). Weanling rats were subjected to lithium/pilocarpine-induced SE or saline injections and were then randomized to either the KD or regular rat diet, both fed ad libitum. One month later, rats were evaluated for visual-spatial memory in the water maze, activity level in the open field test, and emotionality with the handling test. Spontaneous recurrent seizures were measured using videotaping, and seizure susceptibility was tested with flurothyl inhalation. Brains were weighed and examined for mossy fiber sprouting and cell loss. Although rats treated with the KD were active and seemed healthy, their weight gain was substantially lower than that in rats that received regular rat diet. The KD reduced the number of spontaneous seizures but had no discernible effect on flurothyl seizure susceptibility. KD-fed rats, with or without SE, had significantly impaired visual-spatial learning and memory compared with rats that were fed regular diet. The KD had minimal effects on activity level and emotionality. Rats that were treated with the KD had significantly impaired brain growth. No differences in pathology scores between the KD and regular diet groups were seen after SE. Despite reducing the number of spontaneous seizures after SE, the KD resulted in severe impairment in visual-spatial memory and decreased brain growth, with no effect on mossy fiber sprouting. This study raises concerns about the long-term effects of the KD on brain development.

The influence of cognitive reserve on seizure-induced injury.

Status epilepticus (SE) is associated with a significant risk of cognitive impairment. While many factors likely determine cognitive outcome following SE, there is evidence that cognitive ability prior to a neurological insult may be an important determinant of outcome. Patients with greater cognitive abilities or so-called cognitive reserve may be less vulnerable to injury than patients with limited cognitive ability. Here we tested the hypothesis that cognitive abilities prior to SE would be predictive of cognitive outcome. Immature rats were tested in the water maze, a test of visual-spatial memory, and divided into fast and slow learners. Animals were then subjected to SE and retested in the water maze 23 days later. Control rats were tested in the same manner but not subjected to SE. SE resulted in marked impairment in water maze performance. However, no statistical difference was noted in performance between slow and fast learners in either the SE or control group. Likewise, no differences were seen in the histopathology of the slow and fast learners. This study demonstrates that SE adversely effects visual-spatial memory equally in both fast and slow learners and does not support the theory that cerebral reserve plays a major role in cognitive function following a cerebral insult.