Hippocampal Interneurons in Bipolar Disorder

Abstract

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 bipolar and healthy control subjects. Design Whole human hippocampi of 14 bipolar 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 PCR 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 non-pyramidal 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 two groups did not differ in the total number of hippocampal neurons, but the bipolar disorder group showed reduced volume of the non-pyramidal 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 glutamate decarboxylase 1. Conclusions Our results indicate a specific alteration of hippocampal interneurons in bipolar disorder, likely resulting in hippocampal dysfunction.

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

“…In keeping with previous literature, the 2D-DIGE method identified reductions in the expression of hippocampal of parvalbumin (PVALB) in both diagnostic groups, (Konradi et al, 2011a;Konradi et al, 2011b;Schmidt and Mirnics, 2014).…”

“…While some findings are similar for both disorders (Haukvik et al, 2014;Mathew et al, 2014), differences are described in the overall extent and in the premorbid manifestation of hippocampal volume reductions (Ellison-Wright and Bullmore, 2010;Fornito et al, 2009;Fusar-Poli et al, 2011;Fusar-Poli et al, 2012), which may relate to different underlying biological mechanisms (Bellivier et al, 2013). At the histological and cellular level, several studies have found hippocampal neurons of compromised morphology and organization, as well as pre-synaptic and dendritic deficits, in schizophrenia (Harrison, 2004) and bipolar disorder (Konradi et al, 2011b). Amongst the neuron populations affected by these changes, GABAergic interneurons, and particularly those of the fast-spiking basket-and chandelier type, have come into the focus in schizophrenia and bipolar disorder research, mainly because of solid evidence for widespread reductions in the concentration of proteins typically expressed by fast-spiking cells such as GAD67, somatostatin, and parvalbumin (Lewis et al, 2005;Woo et al, 1997) in several cortical regions (Hashimoto et al, 2008).…”

“…Amongst the neuron populations affected by these changes, GABAergic interneurons, and particularly those of the fast-spiking basket-and chandelier type, have come into the focus in schizophrenia and bipolar disorder research, mainly because of solid evidence for widespread reductions in the concentration of proteins typically expressed by fast-spiking cells such as GAD67, somatostatin, and parvalbumin (Lewis et al, 2005;Woo et al, 1997) in several cortical regions (Hashimoto et al, 2008). In the hippocampus, such changes have been found particularly in the cornu ammonis areas 2 and 3 (CA2/3) and the stratum oriens of CA1 in schizophrenia (Heckers and Konradi, 2002;Zhang and Reynolds, 2002) (Benes et al, 2007), and in CA 2/3 in bipolar disorder (Konradi et al, 2011b). Because fastspiking GABAergic interneurons synapse onto the spike-initiating region of pyramidal cells, they are thought to possess key controlling properties within the overall firing patterns of brain networks (Lisman et al, 2008).…”

Increased Seizure Susceptibility in a Mouse with Diacylglycerol Kinase <i>β</i> Deficiency

“…In the hippocampal CA3 region of DGKβ KO mice, the number of parvalbumin-positive cells was decreased (vs. WT controls), which would increase the susceptibility of DGKβ KO mice to seizure. Interestingly, the number of parvalbumin positive interneuron is decreased in the hippocampus of patients with bipolar disorder, too [11,21,22]. We reported ealier that DGKβ KO mice display mania-like behavior [8], and others have reported that a splice variant at the COOH-terminal of DGKβ is related to bipolar disorder [23].…”

In Vivo Hippocampal Subfield Volumes in Schizophrenia and Bipolar Disorder

“…Postmortem studies have demonstrated smaller pyramidal neuron cell bodies (13,14), reduced dendritic spine density (15), and reduced interneuron density and number (16)(17)(18) in the hippocampi of patients with schizophrenia and bipolar disorder. The postmortem cellular findings differ among subfields, with CA4 showing more prominent pyramidal soma reduction than CA1 in patients with schizophrenia (16) and CA3 showing decreased number of mossy fiber synapses in patients with schizophrenia (15) as well as a significant reduction of somatostatin-positive neurons in CA1 and parvalbumin-positive neurons in CA1 and CA4 in patients with bipolar disorder (17). Although postmortem hippocampal neuronal abnormalities are present in both patients with schizophrenia and patients with bipolar disorder, there is evidence of diagnostically specific differences in presubiculum-patients with schizophrenia show reduced somatostatinpositive neuron density compared with patients with bipolar disorder (18).…”