Original articleThe density and spatial distribution of gabaergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia
Introduction
There is now substantial evidence that γ aminobutyric acid (GABA)ergic neurotransmission is deficient in schizophrenia. There are reductions in the amount and activity of the GABA synthesizing enzyme, glutamate decarboxylase (GAD) Impagnatiello et al 1998, Sherman et al 1991, and in the release and uptake of GABA Reynolds et al 1990, Simpson et al 1989. There are also increases in the number of GABAA receptors Benes et al 1992, Hanada et al 1987, Impagnatiello et al 1998 and abnormal levels of the messenger RNAs (mRNA) encoding a subunit of the GABAA receptor (Huntsman et al 1998). Reduced numbers of small, presumed inhibitory, interneurons have been reported in layer 2 in the anterior cingulate cortex (ACC) (Benes et al 1991), whereas in the prefrontal cortex, reduced numbers of neurons expressing the mRNA for the 67-kd isoform of GAD (GAD67) Akbarian et al 1995, Volk et al 2000 have been described. As there is no consistent evidence for total cortical neuronal loss in schizophrenia Cotter et al 2001, Ongur et al 1998, Selemon et al 1995, these findings suggest that there is a specific deficit in the inhibitory local circuit neurons in this disorder.
The calcium binding proteins (CBPs), calbindin-D28K (CB), calretinin (CR), and parvalbumin (PV) are present in distinct populations of nonpyramidal GABAergic local circuit neurons in the primate cortex Conde et al 1994, DeFelipe 1997, Lund and Lewis 1993. Parvalbumin is expressed predominantly in the wide arbor (basket) and chandelier subpopulations of GABAergic neurons. Calretinin is expressed by bipolar cells, double bouquet neurons, and Cajal-Retzius cells, and CB labels predominantly double bouquet neurons. The CBPs, CB in particular, also weakly label pyramidal neurons, and certain specific and nonspecific thalamocortical projection systems (Jones and Hendry 1989). Although previous studies have used these CBPs as markers of GABAergic neurons in the prefrontal cortex in schizophrenia, these have not yielded consistent results. These studies have shown both increases (Davis and Lewis 1995) and reductions (Reynolds et al 2000) in the density of CB-immunoreactive (IR) neurons; no changes in the density of CR-IR neurons Davis and Lewis 1995, Reynolds and Beasley 2001 and reductions (Beasley and Reynolds 1997, Reynolds et al 2000 or normal density (Woo et al 1997) of PV-IR neurons in the prefrontal cortex in schizophrenia, yet increased PV-IR neuron density in the ACC (Kalus et al 1997). It has been proposed that the basis of the GABAergic deficit lies in hypoxic damage to vulnerable neurons during the pre- or perinatal period (Benes 1995), and that loss of vulnerable neuronal populations could account for some of the histopathological changes seen in schizophrenia (Benes 2000). Although studies have shown evidence supportive of a GABAergic abnormality in the ACC in schizophrenia Benes et al 1991, Benes et al 2000, Kalus et al 1997, no study has investigated each of the three main populations of neurons labeled by the CBPs in this region.
In this study we examined the following questions: 1) Is there a deficit in the density of the distinct GABAergic neuronal populations labeled respectively by PV, CR, and CB in the ACC in schizophrenia? 2) Is there an altered pattern of organization of these GABAergic neuronal populations? 3) Are alterations in density and spatial pattern of these neurons specific to schizophrenia, or are they also present in tissue from subjects with bipolar disorder (BPD) and major depressive disorder (MDD)? To answer these questions, we compared the laminar density and the spatial organization of the neurons labeled by PV, CR, and CB in the ACC of 15 schizophrenic subjects, 15 subjects with BPD, and 15 subjects with MDD with those of 15 control subjects.
Section snippets
Participants
Human brain specimens from Brodmann’s area 24 (BA24) were obtained from the Stanley Foundation Brain Consortium. The sample consisted of 60 subjects (15 control subjects, 15 schizophrenics, 15 BPD, and 15 MDD). Diagnoses were made according to DSM-IV criteria. Detailed case summaries were provided on demographic, clinical, and histologic information (see Table 1 for group summary details). All brains underwent clinical neuropathological examination, and none demonstrated evidence of
Neuronal density
Median densities for each of the CBP-IR subpopulations are shown in Figure 3. At the 10% level, mean fixation times for schizophrenic subjects (p = .009), those with BPD (p = .001), and those with depressive disorder (p = .055) were significantly higher than for control subjects. Mean postmortem interval for schizophrenic subjects (p = .038) and those with BPD (p = .085) were also significantly higher than for control subjects. No significant group differences were detected for the remaining
Discussion
In this investigation we have found some evidence for a reduction of over 30% in the density of CB-IR neurons in layer 2 of the ACC in subjects with schizophrenia and BPD; however, we found no statistically significant differences in the density of PV-IR or CR-IR neurons between groups. The study supports the notion that there is a deficit in GABAergic neurotransmission in schizophrenia and shows that these changes are not specific to schizophrenia.
Acknowledgements
Funded by a Clinician Scientist Fellowship to David Cotter, and a project award from the Theodore and Vada Stanley Foundation.
Postmortem brains were donated by the Stanley Foundation Brain Bank Consortium, courtesy of Drs. Llewellyn B. Bigelow, Juraj Cervenak, Mary M. Herman, Thomas M. Hyde, Joel Kleinman, Jose D. Paltan, Robert M. Post, E. Fuller Torrey, Maree J. Webster, and Robert Yolken.
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