Neuronal activity regulates gabaa receptor subunit expression in organotypic hippocampal slice cultures

Holopainen, I.; Laurén, Hanna B.

doi:10.1016/s0306-4522(03)00046-0

Cited by 37 publications

(27 citation statements)

References 32 publications

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“…Hence central dysregulation of these neuropeptides is closely associated with hyperphagia and weight gain. However, many acute responses to leptin do not necessitate altered gene expression as leptin alters the excitability of neurons in the hypothalamus and other regions of the brain (Cowley et al 2001;Dhillon et al 2006;Hommel et al 2006;Spanswick et al 1997). This is consistent with the fact that neurons are sensitive to rapid changes in leptin levels.…”

Section: Discussionsupporting

confidence: 60%

Loss of Leptin Receptors on Hypothalamic POMC Neurons Alters Synaptic Inhibition

Chun

2010

Journal of Neurophysiology

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. Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional status. This plasticity at hypothalamic synapses contributes to the control of food intake and body weight. Here we show that genetic ablation of leptin receptor gene expression in proopiomelanocortin (POMC) neurons (POMC: Lepr Ϫ/Ϫ GFP) induces alterations at synapses on POMC neurons in the arcuate nucleus of the hypothalamus. Our studies reveal that POMC: Lepr Ϫ/Ϫ GFP mice have decreased frequency of spontaneous GABAergic, but not glutamatergic, postsynaptic currents at synapses on POMC neurons. The decay time course of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) onto POMC neurons in POMC: Lepr Ϫ/Ϫ GFP mice is significantly slower than that of sIPSCs in control animals. While analysis of individual miniature IPSCs shows lowered baseline activity, this tonic decrease is associated with an increased amplitude and slow decay of mini-IPSCs onto POMC neurons in POMC: Lepr GFP than in control animals. Therefore our present work demonstrates that loss of leptin signaling in POMC neurons induces synaptic alterations at POMC synapses that may play an essential role in energy homeostasis.

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Section: Discussionsupporting

confidence: 60%

Loss of Leptin Receptors on Hypothalamic POMC Neurons Alters Synaptic Inhibition

Chun

2010

Journal of Neurophysiology

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“…While this remains to be determined, current concepts of up-and downregulation of GABAergic inhibition at the level of a single synapse suggest that regulation of receptor numbers is the main mechanism [4,8]. In cultured hippocampal slices, the expression of GABA A R subunit mRNAs and their proteins increased with the level of neuronal activity [32], and a positive correlation between GABA A R subunit mRNA and the corresponding protein was observed [33]. Thus, the relatively large and involving many subunits mRNA changes that we found are likely to lead to the corresponding changes in the numbers of functional GABA A Rs.…”

Section: Effects Of Endogenous Gaba and Gaba A R Antagonist On Gaba Amentioning

confidence: 98%

Regionally selective effects of GABA on hypothalamic GABAA receptor mRNA in vitro

Volgin

Kubin

2007

Biochemical and Biophysical Research Communications

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We tested whether GABA A receptor (R) subunit mRNA levels are homeostatically influenced by short-term exposure to GABA in two adjacent regions of the posterior hypothalamus. mRNA levels for seven GABA A R subunits and GABA-synthesizing enzyme (GAD) were quantified in the perifornical (PF) and dorsomedial (DM) hypothalamus following superfusion of slices for 90 min with a drug-free medium, GABA uptake blocker with or without GABA A R antagonist, gabazine, or GABA A R agonist with tetrodotoxin. Increasing endogenous GABA decreased mRNAs for all seven GABA A R subunits in the PF, and for three also in the DM, region; gabazine antagonized these effects in the PF region only and increased GAD-65 mRNA. Stimulation of GABA A Rs in the presence of tetrodotoxin decreased mRNA for one GABA A R subunit (β 1 ). We conclude that, in the PF region where GABA facilitates sleep, increased GABA release may limit GABA A R-mediated inhibition, whereas in the DM region, GABA-induced changes are mainly mediated by non-GABA A receptors.

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“…The organotypic hippocampal slice culture is a good model system to study the mechanisms of neurodegeneration. This is because several features of hippocampal circuitry, including the maturation of synapses, receptors, and intrinsic fiber pathways, are preserved in vivo, and the preparation is well suited for prolonged pharmacological treatment and recovery, which would be difficult to perform in an intact animal system (37,38). As shown in Fig.…”

Section: Treatment Of Cultured Hippocampal Slices With A␤1-42 Oligomementioning

confidence: 99%

ERK1/2 Activation Mediates Aβ Oligomer-induced Neurotoxicity via Caspase-3 Activation and Tau Cleavage in Rat Organotypic Hippocampal Slice Cultures

Chong

Shin

Lee

et al. 2006

Journal of Biological Chemistry

163

132

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In this study, we investigated the molecular basis for the altered signal transduction associated with soluble amyloid ␤-protein (A␤) oligomer-mediated neurotoxicity in the hippocampus, which is primarily linked to cognitive dysfunction in Alzheimer disease (AD). As measured by media lactate dehydrogenase levels, and staining with propidium iodide, acute exposure to low micromolar concentrations of the A␤1-42 oligomer significantly induced cell death. This was accompanied by activation of the ERK1/2 signal transduction pathway in rat organotypic hippocampal slices. Notably, this resulted in caspase-3 activation by a process that led to proteolytic cleavage of Tau, which was recently confirmed to occur in AD brains. Tau cleavage likely occurred in the absence of overt synaptic loss, as suggested by the preserved levels of synaptophysin, a presynaptic marker. Moreover, among the pharmacological agents tested to inhibit several kinase cascades, only the ERK inhibitor significantly attenuated A␤1-42 oligomer-induced toxicity concomitant with the reduction of activation of ERK1/2 and caspase-3 to a lesser extent. Importantly, the caspase-3 inhibitor also decreased A␤ oligomer-induced cell death, with no appreciable effect on the ERK signaling pathway, although such treatment was effective in reducing caspase-3 activation and Tau cleavage. Therefore, these results suggest that local targeting of the ERK1/2 signaling pathway to reduce Tau cleavage, as occurs with the inhibition of caspase-3 activation, may modulate the neurotoxic effects of soluble A␤ oligomer in the hippocampus and provide the rationale for symptomatic treatment of AD. Alzheimer disease (AD)2 neuropathology is characterized by key features that include fibrillar amyloid ␤-protein (A␤) deposition into dense senile plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated Tau, and the loss of neurons and synapses in the affected brain region leading to the progressive loss of cognitive function (1, 2). Recent evidence suggests that soluble, prefibrillar, and oligomeric forms of A␤ are acutely toxic (3) and can interfere with synaptic plasticity in the brain, suggesting that this form of the peptide may be responsible for episodic memory deficits, an early symptom of AD, which is linked to hippocampal pathology (4). In fact, soluble A␤ oligomers, also referred as A␤-derived diffusible ligands, strikingly elevated in the AD brain (5-8) are also described in human amyloid precursor protein transgenic mice AD models (9) and can inhibit the long term potentiation (LTP) of synaptic efficiency (10, 11). The pathogenic relevance of this form of A␤ has been substantiated by a newly identified Arctic familial AD mutation, which has an increased propensity to oligomerize (12, 13), and by in vitro data demonstrating potent neurotoxicity upon exposure to soluble oligomer or protofibrils (3,14,15). Moreover, the ultrastructural localization of A␤ oligomer within neuritic processes and at synaptic terminals in AD brains (16,17) further supports...

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Neuronal activity regulates gabaa receptor subunit expression in organotypic hippocampal slice cultures

Cited by 37 publications

References 32 publications

Loss of Leptin Receptors on Hypothalamic POMC Neurons Alters Synaptic Inhibition

Loss of Leptin Receptors on Hypothalamic POMC Neurons Alters Synaptic Inhibition

Regionally selective effects of GABA on hypothalamic GABAA receptor mRNA in vitro

ERK1/2 Activation Mediates Aβ Oligomer-induced Neurotoxicity via Caspase-3 Activation and Tau Cleavage in Rat Organotypic Hippocampal Slice Cultures

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