ABSTRACT
GABAergic interneurons synchronize network activities and monitor information flow. Post-mortem studies have reported decreased densities of cortical interneurons in schizophrenia (SZ) and bipolar disorder (BPD). The entorhinal cortex (EC) and the adjacent subicular regions are a hub for integration of hippocampal and cortical information, a process that is disrupted in SZ. Here we contrast and compare the density of interneuron populations in the caudal EC and subicular regions in BPD type I (BPD-I), SZ, and normal control (NC) subjects. Post-mortem human parahippocampal specimens of 13 BPD-I, 11 SZ and 17 NC subjects were used to examine the numerical density of parvalbumin-, somatostatin- or calbindin-positive interneurons. We observed a reduction in the numerical density of parvalbumin- and somatostatin-positive interneurons in the caudal EC and parasubiculum in BPD-I and SZ, but no change in the subiculum. Calbindin-positive interneuron densities were normal in all brain areas examined. The profile of decreased density was strikingly similar in BPD-I and SZ. Our results demonstrate a specific reduction of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region in BPD-I and SZ, likely disrupting synchronization and integration of cortico-hippocampal circuits.
Subject(s)
Bipolar Disorder/pathology , Interneurons/metabolism , Interneurons/pathology , Parahippocampal Gyrus/pathology , Parvalbumins/metabolism , Schizophrenia/pathology , Somatostatin/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Autopsy , Bipolar Disorder/metabolism , Calbindins , Case-Control Studies , Cell Count , Entorhinal Cortex/metabolism , Entorhinal Cortex/pathology , Female , Hippocampus/metabolism , Hippocampus/pathology , Humans , Male , Middle Aged , Nerve Net/metabolism , Nerve Net/pathology , Parahippocampal Gyrus/metabolism , S100 Calcium Binding Protein G/metabolism , Schizophrenia/metabolism , Young AdultABSTRACT
OBJECTIVE: The cellular substrate of hippocampal dysfunction in schizophrenia remains unknown. We tested the hypothesis that hippocampal interneurons are abnormal in schizophrenia, but that the total number of hippocampal neurons in the pyramidal cell layer is normal. METHODS: We collected whole hippocampal specimens of 13 subjects with schizophrenia and 20 matched healthy control subjects to study the number of all neurons, the somal volume of neurons, the number of somatostatin- and parvalbumin-positive interneurons and the messenger RNA levels of somatostatin, parvalbumin and glutamic acid decarboxylase 67. RESULTS: The total number of hippocampal neurons in the pyramidal cell layer was normal in schizophrenia, but the number of somatostatin- and parvalbumin-positive interneurons, and the level of somatostatin, parvalbumin and glutamic acid decarboxylase mRNA expression were reduced. CONCLUSIONS: The study provides strong evidence for a specific defect of hippocampal interneurons in schizophrenia and has implications for emerging models of hippocampal dysfunction in schizophrenia.
Subject(s)
Hippocampus/pathology , Neurons/pathology , Schizophrenia/pathology , Adult , Aged , Aged, 80 and over , Analysis of Variance , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Case-Control Studies , Cell Count , Female , Gene Expression/drug effects , Gene Expression/physiology , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/metabolism , Humans , Male , Middle Aged , Neurons/classification , Neurons/drug effects , Neurons/metabolism , Parvalbumins/genetics , Parvalbumins/metabolism , Schizophrenia/drug therapy , Somatostatin/genetics , Somatostatin/metabolism , Young AdultABSTRACT
CONTEXT: Postmortem studies have reported decreased density and decreased gene expression of hippocampal interneurons in bipolar disorder, but neuroimaging studies of hippocampal volume and function have been inconclusive. OBJECTIVE: To assess hippocampal volume, neuron number, and interneurons in the same specimens of subjects with bipolar disorder and healthy control subjects. DESIGN: Whole human hippocampi of 14 subjects with bipolar disorder and 18 healthy control subjects were cut at 2.5-mm intervals and sections from each tissue block were either Nissl-stained or stained with antibodies against somatostatin or parvalbumin. Messenger RNA was extracted from fixed tissue and real-time quantitative polymerase chain reaction was performed. SETTING: Basic research laboratories at Vanderbilt University and McLean Hospital. SAMPLES: Brain specimens from the Harvard Brain Tissue Resource Center at McLean Hospital. MAIN OUTCOME MEASURES: Volume of pyramidal and nonpyramidal cell layers, overall neuron number and size, number of somatostatin- and parvalbumin-positive interneurons, and messenger RNA levels of somatostatin, parvalbumin, and glutamic acid decarboxylase 1. RESULTS: The 2 groups did not differ in the total number of hippocampal neurons, but the bipolar disorder group showed reduced volume of the nonpyramidal cell layers, reduced somal volume in cornu ammonis sector 2/3, reduced number of somatostatin- and parvalbumin-positive neurons, and reduced messenger RNA levels for somatostatin, parvalbumin, and glutamic acid decarboxylase 1. CONCLUSION: Our results indicate a specific alteration of hippocampal interneurons in bipolar disorder, likely resulting in hippocampal dysfunction.
