MAILMAN RESEARCH CENTER
Program for Structural and Molecular Neuroscience
Interactions among three neurotransmitters may help us to better understand the schizophrenic brain |
The Program for Structural and Molecular Neuroscience was established in 1982 as the Laboratory for Structural Neuroscience. The research work of the lab is focused on learning how neural circuitry is altered in corticolimbic regions of schizophrenic and manic depressive brain. This program uses a three-pronged approach involving the use of postmortem brain tissue, rodent modeling for postmortem changes and studies of postnatal development. Each of these strategies is summarized below:
Postmortem Studies
For the past 20 years, the work in this laboratory has been systematically pursuing the question of whether there are alterations in the circuitry of the limbic lobe in schizophrenia (SZ) and, more recently, bipolar disorder (BD). By using a variety of cytochemical methods, we have demonstrated that there are preferential changes in the GABA system in layer II of the anterior cingulate cortex (ACCx-II) and sectors CA3 and CA2 of the hippocampus, two sites that receive a prominent innervation from the basolateral nucleus of the amygdala (BLa). The connections between the amygdala and the hippocampus may be particularly important for our understanding of the pathophysiology of neuropsychiatric disorders, Most prominent have been changes observed in the GABA system, but other alterations have also been observed in the glutamate and dopamine systems as well. More recent work has been focusing on the use of molecular approaches to study the limbic lobe in schizophrenia and bipolar disorder. For example, we have been using single (ISH) and double (DISH) in situ hybridization to co-localize mRNA for the NR2A subunit with GAD67 mRNA to explore whether changes in the regulation of the NMDA receptor may be preferentially occurring in GABA cells in these disorders. In addition, we have co-localized single-stranded DNA breaks with and without GAD67 mRNA in order to assess whether apoptosis may be occurring in GABAergic interneurons. These results have suggested that apoptosis may be an active process in bipolar disorder, but one that is suppressed in schizophrenia. Most recently, we have used microarray-based gene expression profiling to serve as a broad screen for changes in the expression of genes associated with a variety of different metabolic and signaling pathways in the cingulate cortex and hippocampus of schizophrenic and bipolar subjects. As predicted from our studies of DNA damage, bipolars show a very pronounced increase of many genes associated with apoptosis, while schizophrenics show a pattern of gene expression that would be less likely to result in apoptotic cell death.
"Partial" Rodent Modeling for Schizophrenia and Bipolar Disorder
To model for microscopic changes in ACCx and HIPP of schizophrenics, we have developed a model in which a GABA-A receptor antagonist picrotoxin is infused into the BLn of the amygdala to simulate a GABA defect in this region. The results of the first study showed changes in GABAergic terminals with a similar subregional distribution to that seen in schizophrenia. More recently, we have extended this work by examining the effects of picrotoxin infusion 96 hrs later and following chronic infusion. Immunocytochemical studies of various markers for the GABA system have suggested that GABA cells may show preferential changes in the hippocampus and anterior cingulate cortex. More recently, we extended this work by using a combination of microarray based gene expression profiling and FRET-based quantitative RT-PCR. Overall, these studies are suggesting that G coupled protein receptors (GPCRs) may play an important role in mediating the effects of amygdalar activation on the response of hippocampal neurons. Our working hypothesis is that the amygdalar contributes to neuronal pathology in psychotic disorders by activating apoptotic cascades via GPCR-mediated signaling pathways, particularly that associated with kRASb regulation of MAPKinase and/or the cyclic AMP-mediated regulation of protein kinase A.
Postnatal Development of the Limbic Lobe
In order to explore the question of whether normal postnatal developmental changes may “trigger” the onset of schizophrenia between 16 and 25 years of age, we have studied normal maturational changes in both human and rodent brain. Earlier studies in 1989 and 1994 had demonstrated pronounced increases in the amount of myelination in the medial temporal lobe of human brain during adolescence. In rodent studies, we have been able to assess more specific neural systems, such as the GABA, dopamine (DA) and serotonin (5HT) systems, all of which have been implicated in schizophrenia and bipolar disorder. For example, the GABA system continues to mature until the equivalent of early adolescence, while DA fibers show a progressive infiltration of the medial prefrontal cortex (anterior cingulate region) until the start of the early adult period. When serotonergic fibers in the dorsal raphe nucleus are lesioned soon after birth, the DA system shows an opportunistic increase in the density of its connections with cingulate neurons. This suggests that these systems are highly plastic and subject to re-arrangements if perturbations of normal development occur.
Stress might also have an adverse effect on the maturation of the DA system. In another set of experiments, we have been able to demonstrate that when stress-related levels of corticosterone (CORT) are administered to pregnant rats, their offspring show an increase of DA inputs to interneurons in rat mPFC, a pattern schizophrenics. This change only occurs if the rats receive a subsequent exposure to CORT during the late postweanling that is remarkably similar to what we have observed in the cingulate cortex of and early adult periods. These findings imply that stress in utero may render an animal more vulnerable to the effects of stress later in life.
More recent work has focused on the question of whether amygdalar fibers are also growing into the cingulate cortex at approximately the same time as DA fibers. Using anterograde tracing, we have been able to show a marked increase of BLn fibers in ACCx that continues into the early adult period.
Official Website
This lab has its own website here.
Personnel
- Francine M. Benes, M.D., Ph.D. - Director, and Director of the Harvard Brain Tissue Resource Center (e-mail)
- Miles G. Cunningham, M.D., Ph.D. - Research Fellow (e-mail)
- Barbara Gisabella, Ph.D. - Assistant Electrophysiologist (e-mail)
- Wilson Woo, MD, Ph.D. - Research Associate (e-mail)
- Maribel Lim Research Assistant to Dr. Woo (email)
- Martin Minns - Research Assistant (e-mail)
- Maureen Medeiros - Assistant Administrator (e-mail)