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Benes F.M.,Program in Structural and Molecular Neuroscience | Benes F.M.,Harvard University
Handbook of Experimental Pharmacology | Year: 2012

Studies of the hippocampus in postmortem brains from patients with schizophrenia and bipolar disorder have provided evidence for a defect of GABAergic interneurons. Significant decreases in the expression of GAD67, a marker for GABA cell function, have been found repeatedly in several different brain regions that include the hippocampus. In this region, nicotinic receptors are thought to play an important role in modulating the activity of GABAergic interneurons by influences of excitatory cholinergic afferents on their activity. In bipolar disorder, this influence appears to be particularly prominent in the stratum oriens of sectors CA3/2 and CA1, two sites where these cells constitute the exclusive neuronal cell type. In sector CA3/2, this layer receives a robust excitatory projection from the basolateral amygdala (BLA) and this is thought to play a central role in regulating GABA cells at this locus. Using laser microdissection, recent studies have focused selectively on these two layers and their associated GABA cells using microarray technology. The results have provided support for the idea that nicotinic cholinergic receptors play a particularly important role in regulating the activity of GABA neurons at these loci by regulating the progression of cell cycle and the repair of damaged DNA. In bipolar disorder, there is a prominent reduction in the expression of mRNAs for several different nicotinic subunit isoforms. These decreases could reflect a diminished influence of this receptor system on these GABA cells, particularly in sector CA3/2 where a preponderance of abnormalities have been observed in postmortem studies. In patients with bipolar disorder, excitatory nicotinic cholinergic fibers from the medial septum may converge with glutamatergic fibers from the BLA on GABAergic interneurons in the stratum oriens of CA3/2 and result in disturbances of their genomic and functional integrity, ones that may induce disruptions of the integration of microcircuitry within this region. © 2012 Springer-Verlag Berlin Heidelberg. Source


Benes F.M.,Program in Structural and Molecular Neuroscience | Benes F.M.,Harvard University
Neuropsychopharmacology | Year: 2010

Schizophrenia is a disorder in which disturbances in the integration of emotion with cognition plays a central role and probably involves several different regions, including the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the hippocampal formation, and basolateral amygdala (BLA). Recent brain imaging studies have reported changes in volume, whereas postmortem studies point to dysfunction of the GABA and glutamate systems in these regions. Microarray-based profiles indicate that complex changes in the expression of genes associated with synaptic transmission and ion channels are involved in GABA cell dysfunction in schizophrenics. Molecular abnormalities vary considerably on the basis of sector and layer, suggesting that the unique connectivity of intrinsic and extrinsic afferents may critical in regulating the activity of genes in specific subpopulations of GABA cells. Projections of the BLA may be of particular importance to the induction of abnormal circuitry in schizophrenia, as their ingrowth during late adolescence and early adulthood may help to trigger the onset of illness in susceptible individuals. A preponderance of cellular and molecular abnormalities has been found in the stratum oriens (SO) of sectors CA3/2 in which BLA afferents provide a robust innervation. These observations have lead to the development of a rodent model for the study of abnormal circuitry in this disorder. For example, single-cell recordings in hippocampal slices exposed to increased activation from the BLA have shown decreases in GABA currents in pyramidal neurons in SO of CA3/2, but not CA1, and support the validity of this model. Overall, the postmortem studies of neural circuitry abnormalities in schizophrenia are beginning to implicate specific cellular, molecular, and electrophysiological mechanism in specific subtypes of cortical neurons defined by their afferent and efferent connectivity within key corticolimbic regions. © 2010 Nature Publishing Group All rights reserved. Source


Gisabella B.,Program in Structural and Molecular Neuroscience | Gisabella B.,Harvard University | Bolshakov V.Y.,Harvard University | Benes F.M.,Program in Structural and Molecular Neuroscience | Benes F.M.,Harvard University
PLoS ONE | Year: 2012

Kainate receptor (KAR) subunits are believed to be involved in abnormal GABAergic neurotransmission in the hippocampus (HIPP) in schizophrenia (SZ) and bipolar disorder. Postmortem studies have shown changes in the expression of the GluR5/6 subunits of KARs in the stratum oriens (SO) of sectors CA2/3, where the basolateral amygdala (BLA) sends a robust projection. Previous work using a rat model of SZ demonstrated that BLA activation leads to electrophysiological changes in fast-spiking interneurons in SO of CA2/3. The present study explores KAR modulation of interneurons in CA2/3 in response to BLA activation. Intrinsic firing properties of these interneurons through KAR-mediated activity were measured with patch-clamp recordings from rats that received 15 days of picrotoxin infusion into the BLA. Chronic BLA activation induced changes in the firing properties of CA2/3 interneurons associated with modifications in the function of KARs. Specifically, the responsiveness of these interneurons to activation of KARs was diminished in picrotoxin-treated rats, while the after-hyperpolarization (AHP) amplitude was increased. In addition, we tested blockers of KAR subunits which have been shown to have altered gene expression in SO sector CA2/3 of SZ subjects. The GluR5 antagonist UBP296 further decreased AP frequency and increased AHP amplitude in picrotoxin-treated rats. Application of the GluR6/7 antagonist NS102 suggested that activation of GluR6/7 KARs may be required to maintain the high firing rates in SO interneurons in the presence of KA. Moreover, the GluR6/7 KAR-mediated signaling may be suppressed in PICRO-treated rats. Our findings indicate that glutamatergic activity from the BLA may modulate the firing properties of CA2/3 interneurons through GluR5 and GluR6/7 KARs. These receptors are expressed in GABAergic interneurons and play a key role in the synchronization of gamma oscillations. Modulation of interneuronal activity through KARs in response to amygdala activation may lead to abnormal oscillatory rhythms reported in SZ subjects. © 2012 Gisabella et al. Source


Ohtsuka N.,Program in Structural and Molecular Neuroscience | Ohtsuka N.,Harvard University | Badurek S.,University of Edinburgh | Badurek S.,European Molecular Biology Laboratory | And 8 more authors.
Genesis | Year: 2013

Postmortem studies have revealed a downregulation of the transcription factor Pax5 in GABAergic neurons in bipolar disorder, a neurodevelopmental disorder, raising the question whether Pax5 in GABAergic neurons has a role in normal brain development. In a genetic approach to study functions of Pax5 in GABAergic neurons, Pax5 was specifically deleted in GABAergic neurons from Pax5 floxed mice using a novel Gad1-Cre transgenic mouse line expressing Cre recombinase in Gad1-positive, that is, GABAergic neurons. Surprisingly, these mice developed a marked enlargement of the lateral ventricles at approximately 7 weeks of age, which was lethal within 1-2 weeks of its appearance. This hydrocephalus phenotype was observed in mice homozygous or heterozygous for the Pax5 conditional knockout, with a gene dosage-dependent penetrance. By QTL (quantitative trait loci) mapping, a 3.5 Mb segment on mouse chromosome 4 flanked by markers D4Mit237 and D4Mit214 containing approximately 92 genes including Pax5 has previously been linked to differences in lateral ventricular size. Our findings are consistent with Pax5 being a relevant gene underlying this QTL phenotype and demonstrate that Pax5 in GABAergic neurons is essential for normal ventricular development. © 2013 Wiley Periodicals, Inc. Source


Subburaju S.,Program in Structural and Molecular Neuroscience | Subburaju S.,Harvard University | Benes F.M.,Program in Structural and Molecular Neuroscience | Benes F.M.,Harvard University
PLoS ONE | Year: 2012

Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD 67 (GAD1) expression and may play a role in γ-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD 67 regulation may result in GABAergic dysfunction, we have developed an in vitro model in which GABA cells are differentiated from the hippocampal precursor cell line, HiB5. Growth factors, such as PDGF, and BDNF, regulate the GABA phenotype by inducing the expression of GAD 67 and stimulating the growth of cellular processes, many with growth cones that form appositions with the cell bodies and processes of other GAD 67-positive cells. These changes are associated with increased expression of acetylated tubulin, microtubule-associated protein 2 (MAP2) and the post-synaptic density protein 95 (PSD95). The addition of BDNF, together with PDGF, increases the levels of mRNA and protein for GAD 67, as well as the high affinity GABA uptake protein, GAT1. These changes are associated with increased concentrations of GABA in the cytoplasm of "differentiated" HiB5 neurons. In the presence of Ca 2+ and K +, newly synthesized GABA is released extracellularly. When the HiB5 cells appear to be fully differentiated, they also express GAD 65, parvalbumin and calbindin, and GluR subtypes as well as HDAC1, DAXX, PAX5, Runx2, associated with GAD 67 regulation. Overall, these results suggest that the HiB5 cells can differentiate into functionally mature GABA neurons in the presence of gene products that are associated with GAD 67 regulation in the adult hippocampus. © 2012 Subburaju, Benes. Source

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