Induction of the GABA Cell Phenotype: An In Vitro Model for Studying Neurodevelopmental Disorders

Subburaju, Sivan; Beneš, Francine M.

doi:10.1371/journal.pone.0033352

Cited by 21 publications

(19 citation statements)

References 57 publications

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“…Moreover, Reelin secreted by GABAergic interneurons reportedly modulates NMDA receptor homeostasis (Campo et al, 2009 ). Although the GABAergic phenotype of hippocampal interneurons is in part modulated by BDNF (Subburaju and Benes, 2012 ), the dramatic increase in presynaptic BDNF protein levels in Bsn -mutant mice did not appear to influence the Reelin-positive subpopulation of GABAergic interneurons in this setting.…”

Section: Discussionmentioning

confidence: 98%

Distinct synaptic and neurochemical changes to the granule cell-CA3 projection in Bassoon mutant mice

Dieni

Nestel

Sibbe

et al. 2015

Front. Synaptic Neurosci.

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Proper synaptic function depends on a finely-tuned balance between events such as protein synthesis and structural organization. In particular, the functional loss of just one synaptic-related protein can have a profound impact on overall neuronal network function. To this end, we used a mutant mouse model harboring a mutated form of the presynaptic scaffolding protein Bassoon (Bsn), which is phenotypically characterized by: (i) spontaneous generalized epileptic seizure activity, representing a chronically-imbalanced neuronal network; and (ii) a dramatic increase in hippocampal brain-derived neurotrophic factor (BDNF) protein concentration, a key player in synaptic plasticity. Detailed morphological and neurochemical analyses revealed that the increased BDNF levels are associated with: (i) modified neuropeptide distribution; (ii) perturbed expression of selected markers of synaptic activation or plasticity; (iii) subtle changes to microglial structure; and (iv) morphological alterations to the mossy fiber (MF) synapse. These findings emphasize the important contribution of Bassoon protein to normal hippocampal function, and further characterize the Bsn-mutant as a useful model for studying the effects of chronic changes to network activity.

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Section: Discussionmentioning

confidence: 98%

Distinct synaptic and neurochemical changes to the granule cell-CA3 projection in Bassoon mutant mice

Dieni

Nestel

Sibbe

et al. 2015

Front. Synaptic Neurosci.

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“…BDNF signaling through TrkB is a key regulator of GABA expression and GAD 67 function during development. 21 , 22 Differentiated HiB5 cells show morphological characteristics of neurons, express post-mitotic neuronal markers, synthesize GABA and release it on stimulation 19 and integrate into the developing hippocampus. 20 …”

Section: Methodsmentioning

confidence: 99%

“…A standard immunofluorescence technique was used to visualize epigenetic factors. 19 Antibodies used included mouse anti-HDAC1 1:750 (Cell Signaling, Danvers, MA, USA; 5356) and rabbit anti-DAXX 1:750 (Santa Cruz, Santa Cruz, CA, USA; sc 7152).…”

Section: Methodsmentioning

confidence: 99%

“…To shed further light on this issue, this study has employed a novel in vitro model in which hippocampal precursor cells are differentiated into neurons with a GABAergic phenotype in vitro . 19 Lentiviral vector (LVV)-based short-hairpin RNAs are used to selectively inhibit short hairpin RNA interference (shRNAi) the expression of HDAC1 and DAXX in cultured neurons with a GABAergic phenotype, so that their ability to regulate the expression of GAD 67 can be investigated without potential interference from the influences of larger neural circuitry in which the GABA cell might be found. The current report explores the question as to whether HDAC1 and DAXX may play a basic role in the cell-autonomous regulation of GAD 67 expression in GABAergic neurons.…”

Section: Introductionmentioning

confidence: 99%

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Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model

et al. 2016

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Schizophrenia (SZ) is associated with GABA neuron dysfunction in the hippocampus, particularly the stratum oriens of sector CA3/2. A gene expression profile analysis of human postmortem hippocampal tissue followed by a network association analysis had shown a number of genes differentially regulated in SZ, including the epigenetic factors HDAC1 and DAXX. To characterize the contribution of these factors to the developmental perturbation hypothesized to underlie SZ, lentiviral vectors carrying short hairpin RNA interference (shRNAi) for HDAC1 and DAXX were used. In the hippocampal GABA neuron culture model, HiB5, transduction with HDAC1 shRNAi showed a 40% inhibition of HDAC1 mRNA and a 60% inhibition of HDAC1 protein. GAD67, a enzyme associated with GABA synthesis, was increased twofold (mRNA); the protein showed a 35% increase. The expression of DAXX, a co-repressor of HDAC1, was not influenced by HDAC1 inhibition. Transduction of HiB5 cells with DAXX shRNAi resulted in a 30% inhibition of DAXX mRNA that translated into a 90% inhibition of DAXX protein. GAD1 mRNA was upregulated fourfold, while its protein increased by ~30%. HDAC1 expression was not altered by inhibition of DAXX. However, a physical interaction between HDAC1 and DAXX was demonstrated by co-immunoprecipitation. Inhibition of HDAC1 or DAXX increased expression of egr-1, transcription factor that had previously been shown to regulate the GAD67 promoter. Our in vitro results point to a key role of both HDAC1 and DAXX in the regulation of GAD67 in GABAergic HiB5 cells, strongly suggesting that these epigenetic/transcription factors contribute to mechanisms underlying GABA cell dysfunction in SZ.

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“…Contextually, it is interesting to note that neurotrophic factors like brain-derived neurotrophic factor (BDNF) play a significant role in microtubule integrity. 90 ) Deficient BDNF is an established pathogenetic factor in schizophrenia 91 – 93 ); importantly, BDNF links the hippocampus deficits in schizophrenia 94 , 95 ) with microtubule abnormalities. 96 , 97 ) Indeed, the microtubule mice model of schizophrenia (STOP-null mice) demonstrates striking aberrations involving hippocampus.…”

Section: Main Subjectsmentioning

confidence: 99%

Understanding Schizophrenia as a Disorder of Consciousness: Biological Correlates and Translational Implications from Quantum Theory Perspectives

Venkatasubramanian

2015

Clin Psychopharmacol Neurosci

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From neurophenomenological perspectives, schizophrenia has been conceptualized as “a disorder with heterogeneous manifestations that can be integrally understood to involve fundamental perturbations in consciousness”. While these theoretical constructs based on consciousness facilitate understanding the ‘gestalt’ of schizophrenia, systematic research to unravel translational implications of these models is warranted. To address this, one needs to begin with exploration of plausible biological underpinnings of “perturbed consciousness” in schizophrenia. In this context, an attractive proposition to understand the biology of consciousness is “the orchestrated object reduction (Orch-OR) theory” which invokes quantum processes in the microtubules of neurons. The Orch-OR model is particularly important for understanding schizophrenia especially due to the shared ‘scaffold’ of microtubules. The initial sections of this review focus on the compelling evidence to support the view that “schizophrenia is a disorder of consciousness” through critical summary of the studies that have demonstrated self-abnormalities, aberrant time perception as well as dysfunctional intentional binding in this disorder. Subsequently, these findings are linked with ‘Orch-OR theory’ through the research evidence for aberrant neural oscillations as well as microtubule abnormalities observed in schizophrenia. Further sections emphasize the applicability and translational implications of Orch-OR theory in the context of schizophrenia and elucidate the relevance of quantum biology to understand the origins of this puzzling disorder as “fundamental disturbances in consciousness”.

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Induction of the GABA Cell Phenotype: An In Vitro Model for Studying Neurodevelopmental Disorders

Cited by 21 publications

References 57 publications

Distinct synaptic and neurochemical changes to the granule cell-CA3 projection in Bassoon mutant mice

Distinct synaptic and neurochemical changes to the granule cell-CA3 projection in Bassoon mutant mice

Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model

Understanding Schizophrenia as a Disorder of Consciousness: Biological Correlates and Translational Implications from Quantum Theory Perspectives

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