Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition.

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2(-/-) mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2(-/-) caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.

Eastern equine encephalitis.

We describe a patient who died from a fulminant presentation of encephalitis. After an exhaustive search, we found no treatable cause. Postmortem PCR analysis of brain tissue led to a diagnosis of eastern equine encephalitis. We have identified several clinical pearls that may assist others in making the diagnosis earlier in the disease course.

Attitudes towards genetic diagnosis in Pakistan: a survey of medical and legal communities and parents of thalassemic children.

OBJECTIVES: It was the aim of this study to assess the attitudes of doctors, medical students, lawyers, parliament members and parents of thalassemic children towards genetic diagnosis in Pakistan. STUDY DESIGN: A cross-sectional descriptive survey was conducted among representative samples. RESULTS: Five hundred and seventy doctors, 49 lawyers, 178 medical students, 89 parents of thalassemic children and 16 members of parliament (MPs) were included in the survey. The groups showed considerable difference in their attitudes towards different aspects of the issue. A large proportion (88.5%) agreed to the idea of genetic diagnostic screening, especially the parents of thalassemic patients. Premarital carrier screening was favored by 77% of the respondents. Prenatal screening was most favored by the parents of thalassemic children (94.4%). Likewise, a majority of parents of thalassemic children were in favor of abortion in case of an affected fetus. Genetic self-screening was also favored most by the parents of thalassemic patients (78.2%). Only 24% of the doctors favored making genetic screening mandatory, whereas 63% of the parents agreed to the idea. CONCLUSION: Attitudes regarding genetic diagnosis are markedly different among various societal groups in Pakistan. The parents of the affected children strongly favor genetic screening as does the medical community, though not as strongly as the parents. The legislative groups, particularly the MPs, are reserved in their support. Genetic diagnosis can help decrease the disease burden in the future. However, it raises a number of ethical issues, which need to be addressed. It is important to educate the population about potential benefits as well as ethical dilemmas involved so that the general public is able to make the right decisions for themselves and their families.

Paternal transmission of complex phenotypes in inbred mice.

BACKGROUND: Inbred mice are genetically identical but nonetheless demonstrate substantial variability in complex behaviors such as activity levels in a novel environment. This variability has been associated with levels of parental care experienced early in development. Although maternal effects have been reported in biparental and uniparental strains, there have been no investigations of paternal effects in non-biparental strains in which offspring are reared exclusively by mothers. METHODS: In the uniparental inbred Balb/cJ mouse strain, we examined the relationship of paternal open-field activity to the activity of both male and female offspring in the open-field. Potential mediators of paternal transmission of behavior were examined, including maternal care, growth parameters, litter characteristics, and time the father was present with the pregnant mother prenatally. RESULTS: An association of paternal open-field activity with the open-field activity of female but not male offspring was found. Variation in maternal postnatal care was associated with female but not male offspring activity in the open-field but did not mediate paternal effects on offspring behavior. Paternal effects on offspring growth parameters were present, but these effects also did not mediate paternal effects on behavior. CONCLUSIONS: Paternal transmission of complex traits in genetically identical mice reared only by mothers suggests a nongenetic mechanism of inheritance potentially mediated by epigenetic factors. The exclusion of multiple mediators of paternal effects on offspring suggests the possibility of germline paternal inheritance via sperm of complex phenotypes in inbred mice. Future studies are required to examine these interesting possibilities.