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Francine M Benes

Publications and source records attributed to Francine M Benes.

16 recordsLinked to original sources
PubMed2005

Regulation of synaptic plasticity in a schizophrenia model.

The pathology of schizophrenia is characterized by increased hippocampal activity at baseline and during auditory hallucinations. Animal-model studies in which the flow of activity to the hippocampus is increased through decreased amygdalar GABAergic inhibition have shown alterations of hippocampal circuitry similar to schizophrenia, but the functional importance of this phenomenon remains unclear. We provide evidence of decreased hippocampal feed-forward and tonic GABA-mediated inhibition in this animal model, complementing increased hippocampal activity seen in neuroimaging and postmortem studies. We demonstrate that GABA dysfunction increases long-term potentiation through activation of the cholinergic system, offering a new mechanism for pharmacological strategies of this disorder.

Animals↗
PubMed2005

A cross-study meta-analysis and three-dimensional comparison of cell counting in the anterior cingulate cortex of schizophrenic and bipolar brain.

Using a two-dimensional cell counting approach, a 1991 study in the anterior cingulate cortex (ACCx) detected a reduction in the density of nonpyramidal neurons in layers II-VI of schizophrenic subjects. Schizophrenics without superimposed mood disturbances showed a 16% decrease in layer II, while schizoaffectives showed a 30% decrease, suggesting that a decreased density of nonpyramidal neurons in layer II of ACCx might vary more strongly with affective disorder than with schizophrenia. Two follow-up studies from this laboratory, one a replication of that reported in 1991 and the other an analysis of tyrosine hydroxylase immunoreactive fibers, were undertaken in ACCx of normal controls and schizophrenics. These three data sets have been combined and a meta-analysis of the density of pyramidal, nonpyramidal and glial cells was performed to explore whether changes in the density of interneurons in ACCx may be a reliable finding in the major psychoses. Not all groups have reported this finding, but several had employed a different cell counting technique (i.e. three dimensional optical dissector), which could help to explain the discrepant findings in schizophrenia and affective disorder. The data from each of three different studies (now designated as studies A, B and C, respectively) have been internally normalized, combined into a single dataset and analyzed using nonparametric statistics. Tissue blocks from a subset of cases in study B (six controls, six schizophrenics and six bipolars) were embedded in celloidin and counted using an "unbiased" three dimensional counting method (study D). The data from studies A and B indicate that the density of nonpyramidal neurons in layer II of ACCx in the schizoaffective and bipolar samples was significantly decreased. In the schizophrenics, the nonpyramidal neurons were also decreased, but only by 15%. All three groups also showed a decrease of pyramidal neurons in layers IV, V and VI, but this difference was significant only in layer IV of the schizophrenics. When data from study C were added, the differences in pyramidal and nonpyramidal neurons were less striking. For study D, the pattern of findings are strikingly similar to those obtained in studies A, B and C, indicating that both 2D and 3D cell counting methodologies are capable of detecting the same differences. Taken together, these results indicate that the earlier finding of a decreased density of nonpyramidal neurons in ACCx of schizophrenics is consistent across non-overlapping subjects and/or methods in four separate studies, and is more pronounced in schizoaffective and bipolar subjects than in schizophrenics without superimposed mood disturbance.

Bipolar Disorder↗
PubMed2004

Differences in the cellular distribution of D1 receptor mRNA in the hippocampus of bipolars and schizophrenics.

Several lines of evidence have pointed to a role of the dopamine system in the pathophysiology of schizophrenia. A recent postmortem study demonstrated a selective decrease of tyrosine hydroxylase fibers on pyramidal neurons in sector CA2 in the hippocampus of schizophrenics. Although both brain imaging and postmortem studies have examined the distribution of the D1 receptor in the prefrontal and cingulate cortex, no study to date has examined its expression of mRNA using a high-resolution autoradiographic approach. In order to further assess whether the regulation of the dopamine D1 receptor is altered in hippocampal neurons in this disorder, we used in situ hybridization (ISH) to measure the expression of messenger RNA for this receptor in the dentate gyrus and sectors CA1-4. Both the number of cells expressing D1 mRNA and the amount of expression per cell were measured in 15 schizophrenic, 15 bipolar disorder, and 15 normal control subjects. The results show a significant (21%) and selective decrease in D1 mRNA expression in sector CA3 of schizophrenic subjects. First-degree relatives of schizophrenics did not show any differences in either the expression of D1 mRNA per cell or the number of cells expressing this mRNA when compared to a separate group of normal controls matched for age and PMI. Subjects with bipolar disorder also showed a significant (25%) and selective increase of D1 mRNA expression in sector CA2. Other hippocampal sectors did not show significant changes. These findings in schizophrenics and bipolars were also associated with inverse changes in the overall number of neurons expressing D1 mRNA in sectors CA3 and CA2, respectively. This study shows diagnosis-specific changes in D1 mRNA expression in the hippocampus of schizophrenic versus bipolar subjects and suggests that this neuromodulatory system may show distinct changes in the pathophysiology of the two disorders.

Adult↗
PubMed2004

Molecular evidence for mitochondrial dysfunction in bipolar disorder.

BACKGROUND: The disease mechanism of bipolar disorder remains unknown. Recent studies have provided evidence for abnormal gene expression in bipolar disorder. OBJECTIVE: To determine the expression of 12558 nuclear genes in the human hippocampus in healthy control subjects and those with bipolar disorder or schizophrenia. DESIGN: We used gene arrays to study messenger RNA expression. Data were verified with a real-time quantitative polymerase chain reaction assay. SUBJECTS: We studied 10 healthy control subjects, 9 subjects with bipolar disorder, and 8 subjects with schizophrenia. RESULTS: The expression of nuclear messenger RNA coding for mitochondrial proteins was significantly decreased in the hippocampus in subjects with bipolar disorder but not in those with schizophrenia. Subjects with bipolar disorder were characterized by a pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation and the adenosine triphosphate-dependent process of proteasome degradation. CONCLUSIONS: These findings point toward a widespread dysregulation of mitochondrial energy metabolism and downstream deficits of adenosine triphosphate-dependent processes in bipolar disorder.

Adult↗
PubMed2004

Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder.

BACKGROUND: Disturbances of gamma-aminobutyric acid interneurons in the cerebral cortex contribute to the pathophysiology of schizophrenia and bipolar disorder. The activity of these neurons is, in turn, modulated by glutamatergic inputs furnished by pyramidal neurons. OBJECTIVE: To test the hypothesis that glutamatergic inputs onto gamma-aminobutyric acid interneurons via the N-methyl-d-aspartate (NMDA) receptor are altered in the anterior cingulate cortex in schizophrenia and bipolar disorder. DESIGN: A double in situ hybridization technique was used to simultaneously label the messenger RNA (mRNA) for the NMDA NR(2A) subunit with (35)sulfur and the mRNA for the 67-kDa isoform of the gamma-aminobutyric acid synthesizing enzyme glutamic acid decarboxylase (GAD(67)) with digoxigenin. SETTING: Postmortem human brain studies. PARTICIPANTS: We studied 17 subjects with schizophrenia, 17 subjects with bipolar disorder, and 17 normal control subjects. RESULTS: The density of all GAD(67) mRNA-containing neurons was decreased by 53% and 28%, in layers 2 and 5, respectively, in subjects with schizophrenia, whereas in subjects with bipolar disorder there was a 35% reduction in layer 2 only. For GAD(67) mRNA-containing neurons that co-expressed NR(2A)mRNA, their numerical density was decreased by 73% and 52%, in layers 2 and 5, respectively, in subjects with schizophrenia and by 60% in layer 2 in those with bipolar disorder. In the schizophrenia group, the density of the GAD(67)mRNA-containing neurons that did not co-express NR(2A)mRNA was also decreased by 42% in layer 2. In both disease groups, the expression level of NR(2A)mRNA in GAD(67) mRNA-containing cells was unaltered. CONCLUSIONS: The density of gamma-aminobutyric acid interneurons that express the NMDA NR(2A)subunit appears to be decreased in schizophrenia and bipolar disorder. Future studies will address whether subpopulations of these neurons may be differentially affected in the 2 conditions.

Adult↗
PubMed2004

Long-term effects of amygdala GABA receptor blockade on specific subpopulations of hippocampal interneurons.

Growing evidence indicates that the amygdala modulates hippocampal functions. To test the hypothesis that this modulation may involve long-lasting effects on interneuronal networks in the hippocampus, changes in the expression of neurochemical markers specific for different interneuronal subpopulations were assessed in adult rats 96 h following acute infusion of low doses of the GABAA receptor antagonist picrotoxin into the amygdala. The numerical density (Nd) of somata showing immunoreactivity (IR) for parvalbumin (PVB) was decreased in dentate gyrus (DG) and the CA4-2 region, while that of calretinin (CR)-IR was decreased in DG and CA2. The Nd of calbindin D28k (CB)-IR somata was decreased in CA3-2. The densities of axon terminals arising from PVB-IR and cholecystokinin (CCK)-IR basket neurons were also altered, with those of CCK-IR terminals increased across all sectors, while PVB-IR terminals were decreased only in the CA region. Increases in CCK-IR terminals were paralleled by increases of terminals with IR for the 65-kD isoform of glutamate decarboxylase (GAD65). Mixed-effects statistical models, adapted specifically for these analyses, indicated that perturbations of amygdalar inputs to the hippocampus significantly alter the drive that hippocampal PVB-, CR-, and CB-IR neurons within the dentate gyrus/CA4 region exercise on CCK-IR terminals within the same region as well as in CA3-1. These results suggest that amygdalar modulation of specific neuronal subpopulations may induce lasting and far-reaching changes in the hippocampus during normal functioning, as well as in diseases involving a disruption of amygdalar activity. In particular, changes in specific interneuronal markers within selective hippocampal sectors detected in the present results are strikingly similar to those reported in this region in schizophrenia. These similarities suggest that, in this disease, a disruption of GABAergic transmission within the amygdala may play a significant role in the induction of abnormalities in the hippocampus.

Algorithms↗
PubMed2003

DNA fragmentation decreased in schizophrenia but not bipolar disorder.

BACKGROUND: Apoptosis is thought to play a role in neuronal pathology in schizophrenia and bipolar disorder. METHODS: To test this hypothesis, the Klenow method for in situ end-labeling of single-stranded DNA breaks was applied to anterior cingulate cortex from 18 healthy controls, 18 schizophrenic subjects, and 10 bipolar subjects. RESULTS: An unexpected reduction (71%) in Klenow-positive nuclei was found in schizophrenic but not in bipolar cortexes. CONCLUSIONS: To our knowledge to date, this is the first demonstration that there is much less DNA fragmentation in individuals with schizophrenia than in healthy controls and bipolar subjects, which raises a key question as to whether this alteration represents an adaptive or nonadaptive change in the regulation of intracellular signaling and mitochondrial oxidative pathways associated with apoptosis.

Adolescent↗
PubMed2003

Deserving the last great gift.

If there is part of us that we equate with our "self," it is surely the brain. What feelings and expectations, then, are stirred if we decide to give this part of ourselves--or the brain of a loved one--to be sliced, labeled, frozen, and shipped to a laboratory somewhere in the world to be used for research? The director of one of the world's largest brain banks discusses the ethical challenges, implied obligations, and standards of behavior that brain banks must meet to earn and retain the trust of those who give the last great gift--one now indispensable for progress against illnesses ranging from Alzheimer's disease to schizophrenia.

Biomedical Research↗
PubMed2002

Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala.

Auditory information critical for fear conditioning, a model of emotional learning, is conveyed to the lateral nucleus of the amygdala via two routes: directly from the medial geniculate nucleus and indirectly from the auditory cortex. Here we show in the cortico-amygdala pathway that learned fear occludes electrically induced long-term potentiation (LTP). Quantal analysis of the expression of LTP in this pathway reveals a significant presynaptic component reflected in an increase in probability of transmitter release. Conditioned fear also is accompanied by the enhancement in transmitter release at this cortico-amygdala synapse. These results indicate that the synaptic projections from the auditory cortex to the lateral amygdala are modified during the acquisition and expression of fear to auditory stimulation, thus further strengthening the proposed link between LTP in the auditory pathways to the amygdala and learned fear.

Amygdala↗
PubMed2002

Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia.

BACKGROUND: Expression of messenger RNA (mRNA) for the gamma-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), in the prefrontal cortex and the number of GABAergic neurons in the hippocampus are reduced in schizophrenia and bipolar disorder. We tested the hypothesis that the expression of the 2 isoforms, one 65 kd (GAD(65)) and the other 67 kd (GAD(67)), is differentially affected in the hippocampus in schizophrenia and bipolar disorder. METHODS: Hippocampal sections from 15 subjects in 3 groups (control subjects and subjects with schizophrenia and bipolar disorder) were studied using an in situ hybridization protocol with sulfur 35-labeled complementary riboprobes for GAD(65) and GAD(67) mRNA. Emulsion-dipped slides were analyzed for the density of GAD mRNA-positive neurons in 4 sectors of the hippocampus and for the cellular expression level of both GAD mRNAs. RESULTS: The density of GAD(65) and GAD(67) mRNA-positive neurons was decreased by 45% and 43%, respectively, in subjects with bipolar disorder, but only 14% and 4%, respectively, in subjects with schizophrenia. The decreased density of GAD(65) mRNA-positive neurons in subjects with bipolar disorder was significant in sectors CA2/3 and dentate gyrus, and that of GAD(67) mRNA-positive neurons was significant in CA4, but not other hippocampal sectors. Cellular GAD(65) mRNA expression was significantly decreased in subjects with bipolar disorder, particularly in CA4, but not in schizophrenic subjects. Cellular GAD(67) mRNA expression was normal in both groups. CONCLUSION: We have found a region-specific deficit of GAD(65) and GAD(67) mRNA expression in bipolar disorder.

Adult↗