LIMBIC LOBE CIRCUITRY IN RELATION TO SCHIZOPHRENIAAND BIPOLAR DISORDER
Laboratories for Structural Neuroscience, McLean Hospital
Francine M. Benes, M.D., Ph.D., Sabina Berretta, M.D., Stephan Heckers, M.D., Miles G. Cunningham, M.D., Ph.D., Fabio Bordi, Ph.D., Nicholas Lange, Sci.D.
This is a multi-disciplinary research program that uses a combination of neuroanatomic, electrophysiological, molecular and cellular approaches to pursue a two-pronged strategy for characterizing limbic lobe circuitry in relation to the major psychoses, normal and abnormal development and exposure to neuroleptic drugs. Over the past 20 years, a variety of quantitative microscopic approaches to identify discrete alterations in the intrinsic circuitry in layer II of the anterior cingulate cortex and sectors CA3 and CA2 of hippocampal formation. Taken together, these changes have suggested that there may be reductions in the activity of the GABA system and increases of glutamatergic tone. In ACCx-II, there also appears to be a "mis-wiring" of dopaminergic inputs to pyramidal and nonpyramidal neurons. The subregional distribution of abnormalities in SZ and BD has suggested that projections from the basolateral nucleus of the amygdala may play a central role in the pathophysiology of both disorders. A 'partial' rodent model in which the outflow of excitatory activity from this nucleus is increase is being used to gain new insights into how the changes seen in SZ and BD might have been induced. To answer the critical question as to why schizophrenia begins between 16 and 20 years of age, the postnatal development of intrinsic and extrinsic connections to the limbic lobe have also been studied. Specifically, glutamatergic fibers from the amygdala and dopaminergic fibers from the midbrain are actively growing into ACCx during the equivalent of adolescence, suggesting the possibility that these systems might play a role in "triggering" the onset of abnormal function in individuals who carry the vulnerability for SZ and BD. Both in vivo and in vitro electrophysiological recording techniques are being used to characterize the limbic lobe activity in relation to normal development in animals in which abnormalities of GABAergic modulation have been induced. In addition, a combination of laser microdissection of single neurons and gene expression profiling are being used to identify candidate genes that are up- or down-regulated in developing and experimentally-manipulated rodents.
Key Words: GABA, glutamate, dopamine, plasticity, development, cingulate cortex, hippocampus, amygdala, stress, excitotoxicity, apoptosis.
Grant Support: NIMH: 5R01 MH42261-13 (FMB) Quantitative Analyses of the Corticolimbic System in Schizophrenic Brain; 5K05 MH00423-20 (FMB) Corticolimbic Circuitry in Relation to Schizophrenia (Research Scientist Award); 5PO3 MH31154-20 (P. Holzman) Collaborative Biological Studies of Schizophrenia; 5RO1 MH31862-21 (FMB) Brain Tissue Resource for Neuropsychiatric Research; 1R21MH/NS62822-02 (FMB) Hippocampal Gene Expression in Schizophrenia; 1P50 MH60450-02 (J.T. Coyle) Neurobiology of Schizophrenia: Studies of Amygdalo-Hippocampal Circuitry.
Program Site: Mailman Research Center, McLean Hospital
Program Director: Francine M. Benes, M.D., Ph.D., Laboratories for Structural Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478; E-mail: benesf@mclean.harvard.edu .
Contact Person: Maureen Medieros, Administrative Secretary TEL: 617-855-2401; FAX: 617-855-3199.
Representative Publications:
Benes, F.M, Turtle, M., Khan, Y., Farol, P. Myelination of a key relay in the hippocampal formations occurs during childhood, adolescence and adulthood in human brain. Archives of General Psychiatry. 1994; 51: 477-484.
Benes, F.M. Corticolimbic circuitry and the development of psychopathology during childhood and adolescence. In: Development of the Prefrontal Cortex: Evolution, Neurobiology and Behavior. Goldman-Rakic, P.S., Krasnegor, N., Lyon, R. (Eds.) Paul H. Brooks Publishing Co., Baltimore, MD, 1997; 211-239.
Stone, D., Walsh, J., Benes, F.M. Localization of cell preferentially expressing GAD67, but not GAD65 transcripts in the rat hippocampus. A double in situ hybridization study. Molecular Brain Research. 1999; 71: 201-209.
Benes, F.M. Emerging principles of altered neural circuitry in schizophrenia. Brain Research Reviews 2000; 31: 251-269.
Berretta, S., Munno, D.W., Benes, F.M. Activation of amygdalar afferents alters GABA terminals in hippocampus. A 'partial' rodent model for schizophrenia. Journal of Comparative Neurology; 2001; 431:129-138.
Benes, F.M., Taylor, J.B., Cunningham, M.G. Convergence and competition of monoaminergic fibers on intrinsic neurons in rat medial prefrontal cortex during the postnatal period. Cerebral Cortex 2000; 10:1014-1027
Stone, D.J., Walsh, J.P., Sebro, R., Stevens, R., Pantazopolous, H., Benes, F.M. Effects of pre- and postnatal corticosterone exposure on the rat hippocampal GABA system. Hippocampus 2001; 11:492-507.
Benes, F.M., Berretta, S. The GABA Cell: Implications for Understanding Schizophrenia and Bipolar Disorder. Neuropsychopharmacology 2001; 25:1-27.