| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Chuhma, Nao Anderson, Stewart A. Moore, Holly Ross, Margaret Elizabeth Chohan, Muhammad O. Schobel, Scott A. Merker, Robert J. Gilani, Ahmed I. Inan, Melis Small, Scott A. Chaudhury, Nashid H. Paskewitz, Samuel Glickstein, Sara Xu, Qing |
| Description |
Author Affiliation: Gilani AI ( New York State Psychiatric Institute, New York, NY 10032); Chohan MO ( New York State Psychiatric Institute, New York, NY 10032); Inan M ( Department of Psychiatry andFeil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065.); Schobel SA ( New York State Psychiatric Institute, New York, NY 10032); Chaudhury NH ( New York State Psychiatric Institute, New York, NY 10032); Paskewitz S ( New York State Psychiatric Institute, New York, NY 10032); Chuhma N ( New York State Psychiatric Institute, New York, NY 10032); Glickstein S ( Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065.); Merker RJ ( New York State Psychiatric Institute, New York, NY 10032); Xu Q ( Department of Psychiatry and.); Small SA ( Neurology, Columbia University, New York, NY 10032); Anderson SA ( Department of Psychiatry and hm2035@columbia.edu andersons3@email.chop.edu mer2005@med.cornell.edu.); Ross ME ( Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065 hm2035@columbia.edu andersons3@email.chop.edu mer2005@med.cornell.edu.); Moore H ( New York State Psychiatric Institute, New York, NY 10032); |
| Abstract |
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. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
20 |
| Volume Number |
111 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2014-05-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Hippocampus Embryology Interneurons Cytology Neural Inhibition Stem Cell Transplantation Animals Cognition Disorders Physiopathology Cyclin D2 Genetics Disease Models, Animal Dopamine Metabolism Mice Mice, Inbred C57BL Mice, Knockout Neuronal Plasticity Physiology Parvalbumins Psychotic Disorders Stem Cells Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
