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Benes, Francine

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Benes

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Francine

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Benes, Francine
Author's Publications: search.filters.isAuthorOfPublication.f656e969-9d29-4e6d-89fb-a28b049d2fc4

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    Variability of DNA Methylation within Schizophrenia Risk Loci across Subregions of Human Hippocampus
    (MDPI, 2017) Ruzicka, W. Brad; Subburaju, Sivan; Benes, Francine
    Identification of 108 genomic regions significantly associated with schizophrenia risk by the Psychiatric Genomics Consortium was a milestone for the field, and much work is now focused on determining the mechanism of risk associated with each locus. Within these regions, we investigated variability of DNA methylation, a low-level cellular phenotype closely linked to genotype, in two highly similar cellular populations sampled from the human hippocampus, to draw inferences about the elaboration of genotype to phenotype within these loci enriched for schizophrenia risk. DNA methylation was assessed with the Illumina HumanMethylation450 BeadArray in tissue laser-microdissected from the stratum oriens of subfield CA1 or CA2/3, regions having unique connectivity with intrinsic and extrinsic fiber systems within the hippocampus. Samples consisted of postmortem human hippocampus tissue from eight schizophrenia patients, eight bipolar disorder patients, and eight healthy control subjects. Within these genomic regions, we observed far greater difference in methylation patterns between circuit locations within subjects than in a single subregion between subjects across diagnostic groups, demonstrating the complexity of genotype to phenotype elaboration across the diverse circuitry of the human brain.
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    Induction of the GABA Cell Phenotype: An In Vitro Model for Studying Neurodevelopmental Disorders
    (Public Library of Science, 2012) Subburaju, Sivan; Benes, Francine
    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 c-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.
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    Kainate Receptor-Mediated Modulation of Hippocampal Fast Spiking Interneurons in a Rat Model of Schizophrenia
    (Public Library of Science, 2012) Gisabella, Barbara; Bolshakov, Vadim; Benes, Francine
    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.