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Biomedical subjects

F M Benes

Publications and source records attributed to F M Benes.

At least 37 records · Page 2Linked to original sources
PubMed1998

A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives.

BACKGROUND: Recent studies have suggested that there may be a preferential decrease of "nonpyramidal" neurons (NPs) in several corticolimbic regions of schizophrenic (SZ) brain. The current study was undertaken to determine whether a change in the density of pyramidal neurons (PNs) and NPs might be present in the hippocampal formation (HIPP) of SZ brain. METHODS: A spatial counting approach in which the location of each and every PN and NP in the stratum pyramidale of sectors CA1-4 was applied to 11 normal control (CONs) and 10 SZs matched for age and postmortem interval, as well as 4 manic depressive (MD) subjects matched for age. RESULTS: The data indicate that the CONs had approximately 10-20 times as many PNs than NPs in the various HIPP subfields. When the CON data were compared to those for the SZs, both the total number and density of PNs were found to be similar in all four sectors, while NPs were found to be selectively reduced by approximately 40% in CA2 of the SZ group. When the data were broken down according to patients with and without neuroleptic exposure, drug-free SZs showed a significant reduction in the density of NPs in CA2. The 4 MD cases both with and without neuroleptic exposure also showed a similar reduction of NPs in sector CA2. CONCLUSIONS: Taken together, the results of this study suggest that there may be a highly selective decrease in the number of NPs in sector CA2 that could play a contributory role in the pathophysiology of the major psychoses.

Adult↗
PubMed1998

Neonatal raphe lesions increase dopamine fibers in prefrontal cortex of adult rats.

In order to characterize how the dopamine (DA) and serotonin (5HT) systems may be interacting in medial prefrontal cortex (mPFC) during postnatal development, the specific toxin 5,7-dihydroxytryptamine (5,7-DHT) was used to induce lesions of the nucleus raphe dorsalis (NRD) in neonatal rats and the density of tyrosine hydroxylase-immunoreactive varicosities (TH-IRv) was assessed. During the early adult period, lesioned rats showed a significant increase in the density of the TH-IR fibers in layers V and VI when compared with sham-treated animals. These results suggest that postnatal development in medial prefrontal cortex may be associated with a competitive interaction between cortical monoaminergic systems, such that an early disturbance in the development of the 5HT innervation can potentially induce a hyperinnervation of DA fibres.

Animals↗
PubMed1998

High-resolution scatchard analysis shows D1 receptor binding on pyramidal and nonpyramidal neurons.

In order to better understand the mechanism of action of atypical antipsychotic drugs (APDs), it is important to clarify how the dopamine system is integrated within local corticolimbic circuits. Toward this end, a high-resolution (HR) Scatchard technique has been used to measure the relative density (Bmax) and affinity (Kd) of D1 receptors on large neurons (> 100 microm2), on small neurons (< 100 microm2), and in neuropil (NPL) of rat medial prefrontal cortex (mPFC) and to determine the laminar distribution of these receptors for each neuronal compartment. Using [3H] SCH23390 as a ligand, all Kd and Bmax values were found to be similar indicating that D1 receptor activity is not preferentially localized to either large or small neuronal subtypes in mPFC. The density of D1 receptor binding in all three compartments was found to be almost twice as great in layers V and VI, as compared to superficial layers II and III. These results suggest that the blockade of D1 receptors associated with some atypical APDs may involve both pyramidal and nonpyramidal neurons in the PFC.

Animals↗
PubMed1998

Distribution of glutamate decarboxylase65 immunoreactive puncta on pyramidal and nonpyramidal neurons in hippocampus of schizophrenic brain.

Recent studies have reported an increase in GABAA receptor binding activity in several key corticolimbic regions, including the hippocampal formation, of postmortem schizophrenic brain. Because this change has been postulated to represent a compensatory upregulation of this receptor, the current report has sought to determine whether a decrease of glutamate decarboxylase (GAD), the enzyme responsible for the synthesis of GABA, may also be present in the hippocampus of schizophrenic subjects. A standard immunoperoxidase technique, together with a computer-assisted microscopic analysis, has been employed to evaluate the distribution of the 65 kDalton isoform of GAD (GAD65) in 12 normal controls and 13 schizophrenic subjects matched for age and postmortem interval (PMI). The results show no significant difference in the density of GAD65-immunoreactive (-IR) puncta in contact with pyramidal neurons (PN), nonpyramidal neurons (NP), or neuropil (NPL) in sectors CA1-4 and their various sub-laminae. When the data were considered in relation to neuroleptic exposure, a significant positive correlation between the density of GAD65-IR puncta and drug dose was found on both PNs (r = 0.814, P = 0.002; r = 0.777, P = 0.005, respectively) and NPs (r = 0.673, P = 0.023; r = 0.672, P = 0.024, respectively) in sectors CA4 and CA3. A similar result was found in the stratum oriens of CA3 (r = 0.704, P = 0.016) and CA2 (r = 0.774, P = 0.009). In each instance, two neuroleptic free schizophrenics showed the lowest density of GAD65-IR puncta. There was no significant relationship between the density of GAD65-IR puncta with either age or PMI. Taken together with previous data showing an upregulation of GABAA receptor activity in sectors CA3 and CA2, particularly the stratum oriens, this study provides further evidence in support of the hypothesis that an intrinsic defect of GABAergic activity may occur in the hippocampal formation of schizophrenic patients and show dose-related increases in relation to neuroleptic exposure.

Adult↗
PubMed1998

Model generation and testing to probe neural circuitry in the cingulate cortex of postmortem schizophrenic brain.

In the past decade, there has been increased interest in whether discreet alterations of neural circuitry might play a role in the pathophysiology of schizophrenia. In the absence of a readily identifiable histopathology, a variety of sophisticated neurobiological approaches is being applied to the study of this disorder. In one series of investigations, subtle abnormalities have been detected in the anterior cingulate cortex-layer II (ACCx-II) of schizophrenia patients. One of these studies suggested a reduction of nonpyramidal neurons in schizophrenia patients, and it was postulated that this change could give rise to a relative increase of dopaminergic inputs to the remaining gamma-aminobutyric acid (GABA) cells. Although empiric evidence in support of this hypothesis was obtained, a subsequent post hoc analysis, described in this report, has suggested that this change could have occurred irrespective of whether GABA cells are reduced in number. A shift of cortical dopamine afferents from pyramidal to nonpyramidal neurons in ACCx-II seems to provide a more plausible explanation for such a "miswiring." These findings support critical use of model generation and testing as powerful tools for unraveling the nature of altered neural circuitry in postmortem schizophrenic brain.

Autopsy↗
PubMed1997

Uncoupling of GABA(A) and benzodiazepine receptor binding activity in the hippocampal formation of schizophrenic brain.

A recent postmortem study has reported that there is a widespread upregulation of GABA(A) receptor binding activity throughout most subregions of the hippocampal formation of schizophrenic brain. The current study has been undertaken to determine whether the benzodiazepine (BZ) receptor, which is a component of the GABA(A) receptor complex, may also be upregulated in schizophrenics. Using a low-resolution film autoradiographic technique to localize [3H]flunitrazepam binding, the subregional and laminar distribution of specific BZ receptor binding was found to parallel that of the GABA(A) site, except in the area dentata where BZ binding was approximately 73% higher in the outer molecular layer. When BZ receptor binding was compared in the same normal control (n = 15) and schizophrenic (n = 8) cases in which the GABA(A) receptor was analyzed, there were very few differences noted between the two groups, except for small, though significant, increases in the stratum oriens of CA3 (30%), the subiculum (20-30%) and the presubiculum (15-20%) of the patient group. These latter increases overlapped with the subregions and laminae in schizophrenics showing the most marked increases of GABA(A) receptor binding. Using a high-resolution technique to evaluate specific BZ receptor binding on different neuronal subtypes, no difference was observed on either pyramidal or nonpyramidal neurons of sector CA3 where GABA(A) receptor activity had been found to be significantly increased on the latter neuronal subtype. The potential confounding effects of age, postmortem interval and exposure to either benzodiazepine or neuroleptic drugs do not account for the lack of marked differences in BZ receptor binding in the schizophrenic group. Taken together, the results of this study are consistent with the possibility that defective GABAergic integration in schizophrenia may be associated with an uncoupling in the regulation of the GABA(A) and BZ receptors.

Case-Control Studies↗
PubMed1997

Differential distribution of tyrosine hydroxylase fibers on small and large neurons in layer II of anterior cingulate cortex of schizophrenic brain.

A series of recent postmortem investigations of the anterior cingulate cortex in schizophrenic brain have suggested that there may be a loss and/or impairment of inhibitory interneurons in layer II. It has been postulated that changes of this type could secondarily result in a relative increase of dopaminergic inputs to GABAergic interneurons. To test this hypothesis, an immunoperoxidase technique was developed to extensively and reliably visualize tyrosine hydroxylase-immunoreactive (TH-IR) varicose fibers in human postmortem cortex. This method has been applied to the anterior cingulate (ACCx; Brodmann area 24) and prefrontal (PFCx: Brodmann area 10) cortices from a cohort of 15 normal control and 10 schizophrenic cases. The number of TH-IR varicosities in contact with large neurons (LN), small neurons (SN), and neuropil (NPL) was blindly analyzed using a computer-assisted microscopic technique. There was no significant difference in density of TH-IR varicosities in apposition with either LN or SN cell bodies observed in either ACCx or PFCx of schizophrenics when compared to normal controls. The density of varicosities was significantly reduced in NPL of layers V and VI in ACCx, but 2 neuroleptic-free cases did not show this change, suggesting that these decreases of TH-IR varicosities may be related to antipsychotic effects on corticostriatal projection cells in this region. When the density of TH-IR varicosities on SNs was compared to that observed on LNs, both groups showed a higher density on SNs. In ACCx, this pattern was much more pronounced for the schizophrenic group, particularly in layer II where the density on SNs was three times higher than that for LNs (P = 0.01). Unlike the changes in layer V, this latter change in layer II showed no relationship to neuroleptic exposure. There was a positive correlation between age and the density of TH-IR varicosities on SNs of layer II in ACCx; however, the patients were younger than the controls and would have been expected to show a lower density, rather than a higher one, if age considerations had accounted for the group differences. Overall, the results reported here suggest that there are no gross differences in the distribution of TH-IR varicosities in various laminae of the dorsolateral prefrontal cortex. In the anterior cingulate region, however, there may be a significant shift in the distribution of TH-IR varicosities from large neurons to small neurons that occurs selectively in layer II of schizophrenic subjects. Using size criteria, the majority of small neurons are likely nonpyramidal, while the majority of large neurons are predominantly pyramidal in nature. Taken together with other accumulating evidence of preferential abnormalities in this lamina of the cingulate region, the findings reported here are consistent with a model of schizophrenia in which a subtle "miswiring" of ventral tegmental inputs may result in a relative, though not absolute, hyperdopaminergic state with respect to an impaired population of GABAergic interneurons.

Cell Size↗
PubMed1997

What an archaeological dig can tell us about macro- and microcircuitry in brains of schizophrenia subjects.

This commentary on recent postmortem investigations suggests that schizophrenia may involve alterations of corticothalamic and temporolimbic regions of the brain. Although studies of this type are beginning to provide unique insights into the underlying pathophysiology of this disorder, all such investigations are generally hampered by the inability to differentiate between primary and secondary changes within complex macro- and microcircuitry. To overcome this basic epistomological problem, it will be necessary to develop novel strategies for determining how the communication between and within these various brain regions is decompensating, and later, compensating at different stages of the life cycle in schizophrenia.

Archaeology↗
PubMed1997

Meta-analysis of postmortem studies of Alzheimer's disease-like neuropathology in schizophrenia.

OBJECTIVE: To evaluate the hypothesis that patients with schizophrenia who have been treated with neuroleptics have a high rate of Alzheimer's disease-like neuropathology. METHOD: Neuropathological studies indicating the presence or absence of Alzheimer's disease-like neuropathology in the postmortem brains of patients with schizophrenia, normal comparison subjects, and comparison subjects who had affective disorder were evaluated with Mantel-Haenszel chi-square and odds ratio analyses. RESULTS: Ten studies with relevant data were reviewed; none of eight with comparisons indicated that Alzheimer's disease-like neuropathology was more likely to be found in the brains of patients with schizophrenia than in the brains of comparison subjects. CONCLUSIONS: Suggestions that cerebral plaques and neurofibrillary tangles are more common in schizophrenia in association with neuroleptic treatment were not supported.

Aged↗
PubMed1996

Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain.

Recent postmortem studies have reported a marked upregulation of GABAA receptor binding activity in the anterior cingulate and prefrontal cortices of schizophrenic subjects. Because the hippocampal formation is a key corticolimbic region that has also been implicated by both postmortem and brain imaging studies in the pathophysiology of this disorder, the current report has sought to determine whether alterations of GABAA receptor binding might also be detected in this region from 15 normal controls and 8 schizophrenic subjects. Using a low resolution autoradiographic approach, the results show a significant increase of specific GABAA receptor binding activity in the area dentata (granule cell layer), CA4, CA3 (str. oriens, str. pyramidale), subiculum, and presubiculum of the schizophrenic group. The magnitude of the increase was greatest in CA3 and lowest in the CA1 sector. When high resolution analyses were performed on emulsion-coverslip preparations, a modest increase of binding (43%, P = 0.05) was observed on pyramidal, but not non-pyramidal neurons in sector CA1. Rather unexpectedly, GABAA binding in sector CA3 was not significantly different on pyramidal cells, but was almost three-fold higher (P = 0.015) on non-pyramidal neurons of the schizophrenic group. There was no relationship of age or the postmortem interval to the parameters showing significant changes in the schizophrenic group. Moreover, patients both with and without neuroleptic exposure showed upregulation of GABAA receptor binding activity. Taking together the rather modest increase of binding activity in CA1 and the more marked upregulation in CA3, as well as the differential changes on pyramidal neurons of CA1 vs. non-pyramidal neurons in CA3, the findings reported here are consistent with the possibility that a disturbance of brain development could have occurred either perinatally or perhaps even well into the postnatal period, and have given rise to discreet subregional and cellular alterations of disinhibitory GABAergic modulation in sector CA3 of schizophrenics. Overall, the data reported here provide further evidence that alterations of GABAergic activity may occur in the hippocampal formation of schizophrenic patients.

Adult↗
PubMed1996

Increased interaction of dopamine-immunoreactive varicosities with GABA neurons of rat medial prefrontal cortex occurs during the postweanling period.

A double immunofluorescence technique has been used to assess postnatal maturational changes in the extent to which dopamine-immunoreactive (DA-IR) varicose fibers form contacts with gamma-aminobutyric acid (GABA)-immunoreactive (IR) neuronal cell bodies in rat medial prefrontal cortex (mPFCx). Two separate measures of interaction, the percentage of GABA-IR cell bodies having DA-IR varicosities in apposition and the number of such profiles in contact with any given GABA-IR cell, were assessed. Between birth and adulthood, there was a progressive linear increase (r = 0.75, P < or = 0.0005) in the percentage of GABA-IR cell bodies having at least one DA-IR varicosity in apposition. While the number of varicosities in contact with any given GABA cell body showed very little change during the preweanling period, later during the postweanling interval, this parameter increased in a curvilinear fashion toward adult levels (r = 0.81, P < or = 0.0005). Taking together these latter two measures, an index of interaction was found to be 1.8 times higher when adult animals were compared to postweanling rats, and 2.5 times higher when compared to preweanling rats. Overall, these results are consistent with the view that there are late postnatal changes in the extent to which midbrain DA afferents interact specifically with GABAergic interneurons in rat mPFCx.

Animals↗
PubMed1996

Increased density of entorhinal glutamate-immunoreactive vertical fibers in schizophrenia.

Gluatamtergic fibers have been immunocytochemically localized in the entorhinal cortex of postmortem schizophrenic brains. The density of small caliber vertical fibers was higher in schizophrenics than controls, with no significant increase in the number of large caliber fibers. Increased glutamatergic fiber density has been previously reported in the cingulate cortex. It is proposed that increases in glutamatergic fibers from the amygdala may be responsible for these changes and that they may play a central role in the pathophysiology of schizophrenia.

Cadaver↗
PubMed1996

Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects.

Recent investigations have reported a reduced density of interneurons and an increase of GABAA receptor binding occurring preferentially in layer II of the anterior cingulate cortex of schizophrenic subjects [Benes F.M. et al. (1992) J. Neurosci. 12, 924-929]. Since a reduction in the density of interneurons has also been found in layer II of the prefrontal cortex, this study has sought to determine whether an un-regulation of the GABAA receptor binding activity might also be found in this region of schizophrenics. A high-resolution autoradiographic analysis of bicuculline-sensitive [3H]muscimol (GABAA) receptor binding on individual neuron cell bodies in layers II, III, IV and VI has been applied to Brodmann area 10 from normal controls (n = 16) and schizophrenic (n = 7) subjects. A computer-assisted technique has been used under strictly blind conditions to determine whether differences in binding occur in the schizophrenic group. A significant increase of GABAA receptor binding activity has been observed in layers II, III, V and VI in the schizophrenic group. When the binding is expressed as a density with respect to neuronal cell size, there is a gradient of binding across layers II, III, V and VI, with neuronal cell bodies in layer II having the greatest density of grains. When different subpopulations of neurons distinguished according to size criteria are examined separately, large (pyramidal) neurons show significantly higher binding, particularly in layer II, where it was increased by 90% in schizophrenics. Small (non-pyramidal) cells do not show significant differences in binding in schizophrenics, except in layer VI, where there was a 135% increase. Potential confounding effects from age and post mortem interval do not explain the differences between the two groups, because both young and old schizophrenics, as well as schizophrenics with long and short post mortem intervals, showed increased GABAA receptor binding activity when compared to control cases distinguished in a corresponding fashion. These data suggest that there may be a preferential reduction of inhibitory GABAergic inputs to pyramidal neurons, particularly in layer II of the preferential cortex, in schizophrenia. This change could potentially result in an increased excitatory outflow from the prefrontal area to other cortical regions of the schizophrenic brain. Overall, these results are consistent with the idea that reduced amounts of GABAergic activity in the prefrontal cortex could be related to a perinatal disturbance and could be a potentially important component of the pathophysiology of psychosis.

Adult↗
PubMed1995

Postnatal maturation of GABA-immunoreactive neurons of rat medial prefrontal cortex.

A light microscopic immunocytochemical approach has been used to examine the distribution and maturation of gamma-aminobutyric acid- (GABA) containing cells in rat medial prefrontal cortex (mPFC) at progressive postnatal stages. Between P1 and P5, labeled cells in the cortical plate show less differentiated morphological characteristics when compared to cells in the deeper laminae. By P10, however, most labeled cells in superficial laminae show more differentiated characteristics with some having a distinctive multipolar appearance. Between P1 and P5, there is a significant increase (50%) in the density of GABA-containing cells in the superficial laminae, while concurrently there is an overall decreases in the subjacent deeper laminae. As the cortex continues to expand, there is a corresponding decrease in the density of GABA-immunoreactive cells in the outer two-thirds of the cortical mantle until approximately P15, stabilizing at 20-25 cells/100,000 microns2 for all laminae. Between P1 and P15, there is also a significant increase (133%) in the average size of labeled cells, followed by a gradual decrease of 30% between P15 and P41. During P1-7, there is a marked increase in the density of labeled axosomatic terminals in both the superficial (200%) and deep laminae (116%). In the superficial layers, however, the density of labeled terminals again increases by 86% between P12 and P18. In general, the present findings are consistent with the idea that there is a progressive maturation of the intrinsic GABAergic system in rat mPFC in a classic "inside-out" pattern, and this involves extensive postnatal changes occurring during the first 3 postnatal weeks.

Animals↗
PubMed1995

Cellular colocalization of dopamine D1 and D2 receptors in rat medial prefrontal cortex.

In a recent study in rat medial prefrontal cortex (mPFC), a fluorescently coupled, high-affinity ligand for the D1 receptor subtype was localized to nonpyramidal neurons, while a ligand selective for the D2 subtype was found on neurons with a size distribution overlapping with both small pyramidal and large nonpyramidal cells. These observations raised the possibility that a subpopulation of cortical neurons with an intermediate size range may coexpress both the D1 and D2 receptor subtypes. In the present study, the D1 and D2 receptor subtypes have been simultaneously localized in layer VI of rat mPFC using 20 nM SCH 23390-Bodipy and 20 nM N-(p-aminophenethyl) spiperone-Texas red, respectively, in the presence of 100 nM mianserin (5-HT2 receptor antagonist). The localization of receptor binding fluorescence was assessed in paired images using fluoroscein isothiocyanate (FITC) and rhodamine dichroic filters for the D1 and D2 subtypes, respectively. Under the conditions employed here, most cell bodies showed either D1-like or D2-like receptor binding fluorescence, while a colocalization of both fluoroprobes was observed on only 25% of the labeled cells. When the size of each single-labeled cell body was measured using the respective FITC (D1-probe) and rhodamine (D2-probe) epifluorescence filters, the distribution of cells showing only D1-like receptor binding fluorescence was similar to nonpyramidal neurons (68.6 +/- 1.8 microns 2), while that for cells showing only D2-like receptor binding fluorescence was similar to that of both large interneurons and small pyramidal cells (106.9 +/- 2.4 microns 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗