MeCP2 R168X male and female mutant mice exhibit Rett-like behavioral deficits.

Rett syndrome (RTT) is a regressive developmental disorder characterized by motor and breathing abnormalities, anxiety, cognitive dysfunction and seizures. Approximately 95% of RTT cases are caused by more than 200 different mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). While numerous transgenic mice have been created modeling common mutations in MeCP2, the behavioral phenotype of many of these male and, especially, female mutant mice has not been well characterized. Thorough phenotyping of additional RTT mouse models will provide valuable insight into the effects of Mecp2 mutations on behavior and aid in the selection of appropriate models, ages, sexes and outcome measures for preclinical trials. In this study, we characterize the phenotype of male and female mice containing the early truncating MeCP2 R168X nonsense point mutation, one of the most common in RTT individuals, and compare the phenotypes to Mecp2 null mutants. Mecp2(R168X) mutants mirror many clinical features of RTT. Mecp2(R168X/y) males exhibit impaired motor and cognitive function and reduced anxiety. The behavioral phenotype is less severe and with later onset in Mecp2(R168X/+) females. Seizures were noted in 3.7% of Mecp2(R168X) mutant females. The phenotype in Mecp2(R168X/y) mutant males is remarkably similar to our previous characterizations of Mecp2 null males, whereas Mecp2(R168X/+) females exhibit a number of phenotypic differences from females heterozygous for a null Mecp2 mutation. This study describes a number of highly robust behavioral paradigms that can be used in preclinical drug trials and underscores the importance of including Mecp2 mutant females in preclinical studies.

Raw, demographically altered, and composite Halstead-Reitan Battery data in the evaluation of adult victims of nonimpact acceleration forces in motor vehicle accidents.

Data from the Halstead-Reitan Neuropsychological Test Battery were interpreted for 33 adults who had been subjected to nonimpact acceleration forces in motor vehicle accidents. Comparisons with normative data provided by Reitan and Wolfson (1993) identified impaired performance on the Localization component of the Tactual Performance Test and the Category Test and atypical right-left differences on the Tactual Performance Test and Grip Strength. In contrast, comparisons with a normative data set developed by Heaton, Grant, Matthews, and PAR Staff (1991) through T-score conversions produced results that suggested normal cognitive skills. The Neuropsychological Deficit Scale score was one of the clearest indicators of neuropsychological impairment, falling generally well within the mildly impaired range.

Neuropsychologic sequelae of non-impact head injury in an older male.

A male (WDR) over the age of 50 years was assessed neuropsychologically on three occasions within a five-year period following a motor vehicle accident. He exhibited no physical evidence of a direct blow to the head, behavior following the accident appeared to fulfil the medical criteria for "mild" head injury, physical neurological examinations, and CT and MRI scans yielded negative results, and primary medical diagnoses included compensation neurosis and conversion reaction. Despite these medical findings and conclusions, neuropsychologic data consistently reflected severe brain injury, involving maximally the right cerebral hemisphere. The neuropsychologic results are reviewed and discussed, and rehabilitative efforts are described. Medical diagnostic procedures that are designed to address issues of survival and the preservation of life may not always be suitable to the principal interest of the clinical neuropsychologist, who addresses brain-related adaptability.

Arousal-dependent properties of medial septal neurons in the unanesthetized rat.

We have performed a qualitative and quantitative analysis of the electrophysiological properties of medial septal neurons in the unanesthetized rat. The rat's head was held in a stereotaxic apparatus by a painless head-restrained system that was implanted seven days prior to the recording sessions. Extracellular recordings were made in a mixed population of antidromically identified septohippocampal neurons and unidentified medial septal neurons in different states of arousal and in response to peripheral and reticular stimulations. The spontaneous activity as well as the percentage of rhythmically bursting septal neurons varied significantly according to the state of arousal. Higher values were noted in paradoxical sleep (28 imp/s and 94% of bursting neurons) as compared with wakefulness with hippocampal theta rhythm (17.4 imp/s and 64.2% of bursting neurons) and slow wave sleep (12.3 imp/s and 8% of bursting neurons). The frequency of the bursts was significantly higher during paradoxical sleep. In individual medial septal neurons, arousing stimuli and paradoxical sleep could induce rhythmic bursting activity in previously non-bursting neurons provided that they were fast-firing neurons. No differences were noted in the functional characteristics of neurons in the medial septal nucleus as compared with the diagonal band of Broca. When the unanesthetized rats were compared with a group of urethane-anesthetized rats, the spontaneous activity was higher and more irregular in the absence of anesthesia. The percentage of the bursting neurons was significantly lower in the unanesthetized rats (32.3% vs 43.3%). However, the frequency of the bursts was higher (5.9 +/- 0.1 Hz vs 3.5 +/- 0.1 Hz). Since the patterns of activity of medial septal neurons fluctuate in different physiologically relevant states, previous classifications of these neurons made by ourselves and other authors, in urethane-anesthetized rats, may not be appropriate.

Effects of different doses of galanthamine, a long-acting acetylcholinesterase inhibitor, on memory in mice.

The effects of galanthamine, a long-acting acetylcholinesterase inhibitor, on passive avoidance and a modified Morris swim task were studied in mice. Lesions of the nucleus basalis magnocellularis (nBM) produced significant decreases in cortical choline acetyltransferase (ChAT) activity and profound deficits on the 24-h retention of a passive avoidance response and the reversal phase of the swim task. Galanthamine, administered 4 h before testing, improved performance of the two tasks in a dose-dependent fashion. In both tasks, galanthamine produced a U-shaped dose-response curve: the optimal dose was 3.0 mg/kg, IP on passive avoidance and 2.0 mg/kg on the swim task. The improvements in performance were not due to differences in motor activity or sensitivity to electric footshock. Behavioral tolerance did not occur from repeated doses of galanthamine; in fact, prior doses of galanthamine appeared to have a priming effect on later performance. In contrast to the effects in nBM-lesioned mice, galanthamine impaired performance of control mice on both tasks. Several characteristics of galanthamine suggest that it may be effective in treating the central cholinergic deficits in Alzheimer's disease: 1) its ability to attenuate cognitive deficits in nBM-lesioned mice, 2) its relatively long half-life, and 3) its lack of tolerance effects in mice during 2 weeks of repeated dosing.

Galanthamine, an acetylcholinesterase inhibitor: a time course of the effects on performance and neurochemical parameters in mice.

The time course of the effects of the long-acting acetylcholinesterase (AChE) inhibitor, galanthamine, on a spatial navigation task and on AChE and acetylcholine (ACh) levels were investigated in mice. Mice received either saline or ibotenic acid injections into the nucleus basalis magnocellularis (nBM). The control and nBM group were than trained to perform a modified Morris swim task and the time to find the hidden platform was recorded. The nBM group took significantly longer to find the platform than the control group in the reversal phase of testing. Galanthamine attenuated the performance deficit in the nBM-lesioned group in a time-dependent manner, with peak performance at four hours after injection of 5.0 mg/kg galanthamine IP. This dose impaired performance of the task in control mice, with the most severe deficits observed at two hours after injections when motor activity was severely reduced. Galanthamine (5.0 mg/kg IP) significantly decreased cortical AChE activity and significantly increased cortical ACh content in control mice in a time-dependent manner. The time courses of the neurochemical effects, however, did not correlate precisely with the behavioral time course. Galanthamine concentrations up to 1 x 10(-5) M did not affect choline acetyltransferase (ChAT) activity, [3H]hemicholinium-3 (HCh-3) binding to the choline carrier, [3H]quinuclidinylbenzilate (QNB) binding to muscarinic receptors, or [3H]acetylcholine binding to nicotinic receptors in cortical homogenates. AChE activity was inhibited by galanthamine in cortical homogenates with an IC50 of 4.1 x 10(-7) M.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurogenesis of the basal forebrain in euploid and trisomy 16 mice: an animal model for developmental disorders in Down syndrome.

The neurogenesis and early histochemical differentiation of the basal forebrain in trisomy 16 fetal mice and their euploid littermates were examined by combining [3H]thymidine autoradiography with acetylcholinesterase histochemistry. Neurons of the basal forebrain were being born between embryonic day 11 and 15 in both chromosomally normal (euploid) and aneuploid mice. In euploid littermate controls, neurogenesis proceeded along a caudal to rostral gradient with the peak on embryonic day 11 for caudal portions and embryonic day 13 for rostral portions of the basal forebrain. In contrast, in trisomy 16 mice, rostral sections exhibited a peak of neurogenesis on embryonic day 11, 2 days earlier than in their euploid littermate controls. Hypocellularity of the basal forebrain region was noted in trisomy 16 mice; particularly dramatic was the reduction of the population of cells that expressed acetylcholinesterase. This reduction in cell number in the trisomics was not accompanied by a reduction in cell size or by a dramatic change in the distribution of residual neurons when compared to that of euploid littermate controls. Since trisomy 16 mice do not survive the perinatal period, we examined the pattern of acetylcholinesterase expression in normal C57B1/6J mice from embryonic day 16 to postnatal day 5 to determine the postnatal disposition of these neurons. Already at embryonic day 16, fibers staining for acetylcholinesterase penetrated the striatal anlage, in their course towards targets in the cerebral cortices. By postnatal day 5, the previously expansive distribution of basal forebrain neurons had become consolidated in a more ventral and rostral position by the extensive outgrowth of the striatal neurons, a pattern resembling that seen in adult animals.

A long-acting cholinesterase inhibitor reverses spatial memory deficits in mice.

The effects of the long-acting acetylcholinesterase (AChE) inhibitor, galanthamine, on spatial memory were investigated in mice. Mice received ibotenic acid or sham lesions to the nucleus basalis magnocellularis (nBM). Groups of nBM-lesioned and control mice were then trained on a modified Morris swim maze task. Each mouse was first placed on a platform and then into quadrants of the swim tank in a random order. Time required to find the hidden platform was measured. In different phases of testing, the animal had to find a platform that either remained in the same quadrant (reference memory component) or was moved daily (working memory component). The nBM-lesioned mice took significantly longer to find the platform as compared to controls on the working, but not on the reference, memory component of the task. Galanthamine (5.0 mg/kg, IP), given 3.5 hours before testing, improved performance on the working memory task in nBM-lesioned mice by 70% and strikingly impaired performance in controls. Galanthamine's ability to reverse cognitive deficits induced by nBM lesions and its comparatively long half-life suggest that it may be effective in treating the central cholinergic deficits in Alzheimer's disease patients.