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The Depolarizing Action of GABA in Cultured Hippocampal Neurons Is Not Due to the Absence of Ketone Bodies  [PDF]
Jaylyn Waddell, Jimok Kim, Bradley E. Alger, Margaret M. McCarthy
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023020
Abstract: Two recent reports propose that the depolarizing action of GABA in the immature brain is an artifact of in vitro preparations in which glucose is the only energy source. The authors argue that this does not mimic the physiological environment because the suckling rats use ketone bodies and pyruvate as major sources of metabolic energy. Here, we show that availability of physiologically relevant levels of ketone bodies has no impact on the excitatory action of GABA in immature cultured hippocampal neurons. Addition of β-hydroxybutyrate (BHB), the primary ketone body in the neonate rat, affected neither intracellular calcium elevation nor membrane depolarizations induced by the GABA-A receptor agonist muscimol, when assessed with calcium imaging or perforated patch-clamp recording, respectively. These results confirm that the addition of ketone bodies to the extracellular environment to mimic conditions in the neonatal brain does not reverse the chloride gradient and therefore render GABA hyperpolarizing. Our data are consistent with the existence of a genuine “developmental switch” mechanism in which GABA goes from having a predominantly excitatory role in immature cells to a predominantly inhibitory one in adults.
Phenolic Compounds Protect Cultured Hippocampal Neurons against Ethanol-Withdrawal Induced Oxidative Stress  [PDF]
Katalin Prokai-Tatrai,Laszlo Prokai,James W. Simpkins,Marianna E. Jung
International Journal of Molecular Sciences , 2009, DOI: 10.3390/ijms10041773
Abstract: Ethanol withdrawal is linked to elevated oxidative damage to neurons. Here we report our findings on the contribution of phenolic antioxidants (17β-estradiol, p-octyl-phenol and 2,6-di-tert-butyl-4-methylphenol) to counterbalance sudden ethanol withdrawal-initiated oxidative events in hippocampus-derived cultured HT-22 cells. We showed that ethanol withdrawal for 4 h after 24-h ethanol treatment provoked greater levels of oxidative damage than the preceding ethanol exposure. Phenolic antioxidant treatment either during ethanol exposure or ethanol withdrawal only, however, dose-dependently reversed cellular oxidative damage, as demonstrated by the significantly enhanced cell viability, reduced malondialdehyde production and protein carbonylation, compared to untreated cells. Interestingly, the antioxidant treatment schedule had no significant impact on the observed neuroprotection. In addition, the efficacy of the three phenolic compounds was practically equipotent in protecting HT-22 cells in spite of predictions based on an in silico study and a cell free assay of lipid peroxidation. This finding implies that free-radical scavenging may not be the sole factor responsible for the observed neuroprotection and warrants further studies to establish, whether the HT-22 line is indeed a suitable model for in vitro screening of antioxidants against EW-related neuronal damage.
GABA release by hippocampal astrocytes  [PDF]
Juan Mendizabal-Zubiaga,Pedro Grandes,Etienne Audinat
Frontiers in Computational Neuroscience , 2012, DOI: 10.3389/fncom.2012.00059
Abstract: Astrocytes can directly influence neuronal activity through the release of various transmitters acting on membrane receptors expressed by neurons. However, in contrast to glutamate and ATP for instance, the release of GABA (γ-amino-butyric acid) by astrocytes is still poorly documented. Here, we used whole-cell recordings in rat acute brain slices and electron microscopy to test whether hippocampal astrocytes release the inhibitory transmitter GABA. We observed that slow transient inhibitory currents due to the activation of GABAA receptors occur spontaneously in principal neurons of the three main hippocampal fields (CA1, CA3, and dentate gyrus). These currents share characteristics with the slow NMDA receptor-mediated currents previously shown to result from astrocytic glutamate release: they occur in the absence of synaptic transmission and have variable kinetics and amplitudes as well as low frequencies. Osmotic pressure reduction, known to enhance transmitter release from astrocytes, similarly increased the frequency of non-synaptic GABA and glutamate currents. Simultaneous occurrence of slow inhibitory and excitatory currents was extremely rare. Yet, electron microscopy examination of immunostained hippocampal sections shows that about 80% of hippocampal astrocytes [positive for glial fibrillary acidic protein (GFAP)] were immunostained for GABA. Our results provide quantitative characteristics of the astrocyte-to-neuron GABAergic signaling. They also suggest that all principal neurons of the hippocampal network are under a dual, excitatory and inhibitory, influence of astrocytes. The relevance of the astrocytic release of GABA, and glutamate, on the physiopathology of the hippocampus remains to be established.
The GABA-Withdrawal Syndrome: A Model of Local Status Epilepticus  [PDF]
Carmen Silva-Barrat,Jean Champagnat,Christian Menini
Neural Plasticity , 2000, DOI: 10.1155/np.2000.9
Abstract: The GABA-withdrawal syndrome (GWS) is a model of local status epilepticus following the interruption of a chronic GABA infusion into the rat somatomotor cortex. GWS is characterized by focal epileptic electroencephalographic discharges and associated contralateral myoclonus. In neocorticai slices obtained from GWS rats, most neurons recorded in the GABA-infused area are pyramidal neurons presenting bursting properties. The bursts are induced by white-matter stimulation and/or intracellular depolarizing current injection and correlate with a decrease of cellular sensitivity to GABA, caused by its prolonged infusion. This effect is related to a calcium influx that may reduce the GABAA receptormediated inward current and is responsible for the bursting properties. Here we present evidence for the involvement of calcium- and NMDA-induced currents in burst genesis. We also report modulatory effects of noradrenaline appearing as changes on firing patterns of bursting and nonbursting cells. Complementary histochemical data reveal the existence of a local noradrenergic hyperinnervation and an ectopic expression of tyrosine hydroxylase mRNAs in the epileptic zone.
Role of the Proteasome in Excitotoxicity-Induced Cleavage of Glutamic Acid Decarboxylase in Cultured Hippocampal Neurons  [PDF]
Márcio S. Baptista,Carlos V. Melo,Mário Armel?o,Dennis Herrmann,Diogo O. Pimentel,Graciano Leal,Margarida V. Caldeira,Ben A. Bahr,Mário Bengtson,Ramiro D. Almeida,Carlos B. Duarte
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010139
Abstract: Glutamic acid decarboxylase is responsible for synthesizing GABA, the major inhibitory neurotransmitter, and exists in two isoforms—GAD65 and GAD67. The enzyme is cleaved under excitotoxic conditions, but the mechanisms involved and the functional consequences are not fully elucidated. We found that excitotoxic stimulation of cultured hippocampal neurons with glutamate leads to a time-dependent cleavage of GAD65 and GAD67 in the N-terminal region of the proteins, and decrease the corresponding mRNAs. The cleavage of GAD67 was sensitive to the proteasome inhibitors MG132, YU102 and lactacystin, and was also abrogated by the E1 ubiquitin ligase inhibitor UBEI-41. In contrast, MG132 and UBEI-41 were the only inhibitors tested that showed an effect on GAD65 cleavage. Excitotoxic stimulation with glutamate also increased the amount of GAD captured in experiments where ubiquitinated proteins and their binding partners were isolated. However, no evidences were found for direct GADs ubiquitination in cultured hippocampal neurons, and recombinant GAD65 was not cleaved by purified 20S or 26S proteasome preparations. Since calpains, a group of calcium activated proteases, play a key role in GAD65/67 cleavage under excitotoxic conditions the results suggest that GADs are cleaved after ubiquitination and degradation of an unknown binding partner by the proteasome. The characteristic punctate distribution of GAD65 along neurites of differentiated cultured hippocampal neurons was significantly reduced after excitotoxic injury, and the total GAD activity measured in extracts from the cerebellum or cerebral cortex at 24h postmortem (when there is a partial cleavage of GADs) was also decreased. The results show a role of the UPS in the cleavage of GAD65/67 and point out the deregulation of GADs under excitotoxic conditions, which is likely to affect GABAergic neurotransmission. This is the first time that the UPS has been implicated in the events triggered during excitotoxicity and the first molecular target of the UPS affected in this cell death process.
Ali Mahfouzi,?Mohammad Reza Zarrindast
Acta Medica Iranica , 1994,
Abstract: 1) Chronic administration of morphine hydrochloride in the drinking water of mice induced physical dependence. Jumping and diarrhea, two signs of withdrawal, were produced by intraperitoneal (IP) injection of naloxone."n2) Baclofen, bicuculline and picrotoxin decreased the number of mice's jumping episodes and frequency of diarrhea."n3) Muscimol decreased jumping but not diarrhea."n4) The data indicate that GABA-Ergic system is possibly involved in the morphine physical dependence, but further studies are required to elucidate the roles of GABA-A or GABA-B receptor sites in physical dependence.
Hippocampal Oscillations in the Rodent Model of Schizophrenia Induced by Amygdala GABA Receptor Blockade  [PDF]
Tope Lanre-Amos,Bernat Kocsis
Frontiers in Psychiatry , 2010, DOI: 10.3389/fpsyt.2010.00132
Abstract: Brain oscillations are critical for cognitive processes, and their alterations in schizophrenia have been proposed to contribute to cognitive impairments. Network oscillations rely upon GABAergic interneurons, which also show characteristic changes in schizophrenia. The aim of this study was to examine the capability of hippocampal networks to generate oscillations in a rat model previously shown to reproduce the stereotypic structural alterations of the hippocampal interneuron circuit seen in schizophrenic patients. This model uses injection of GABA-A receptor antagonist picrotoxin into the baso-lateral amygdala which causes cell-type specific disruption of interneuron signaling in the hippocampus. We found that after such treatment, hippocampal theta rhythm was still present during REM sleep, locomotion, and exploration of novel environment and could be elicited under urethane anesthesia. Subtle changes in theta and gamma parameters were observed in both preparations; specifically in the stimulus intensity – theta frequency relationship under urethane and in divergent reactions of oscillations at the two major theta dipoles in freely moving rats. Thus, theta power in the CA1 region was generally enhanced as compared with deep theta dipole which decreased or did not change. The results indicate that pathologic reorganization of interneurons that follows the over-activation of the amygdala–hippocampal pathway, as shown for this model of schizophrenia, does not lead to destruction of the oscillatory circuit but changes the normal balance of rhythmic activity in its various compartments.
Long-Term Recording of LTP in Cultured Hippocampal Slices  [PDF]
Ken Shimono,Michel Baudry,Lam Ho,Makoto Taketani,Gary Lynch
Neural Plasticity , 2002, DOI: 10.1155/np.2002.249
Abstract: Long-term potentiation (LTP) was elicited by high frequency stimulation in hippocampal slices cultured on multi-electrode arrays. LTP lasting more than 1 h was recorded in 75% of slices, and a significant number of slices exhibited a non-decaying LTP that lasted more than 48 h. LTP induction was completely and reversibly blocked by an antagonist of the NMDA receptor, APV. Our results suggest the possibility of using chronic recording in hippocampal slices cultured on multi-electrode arrays to study the mechanisms underlying LTP maintenance and stabilization.
The amount of astrocytic GABA positively correlates with the degree of tonic inhibition in hippocampal CA1 and cerebellum
Bo-Eun Yoon, Seonmi Jo, Junsung Woo, Jae-Hoon Lee, Taekeun Kim, Daesoo Kim, C Justin Lee
Molecular Brain , 2011, DOI: 10.1186/1756-6606-4-42
Abstract: Tonic inhibition originates from the sustained activation of high affinity gamma-aminobutyric acid (GABA) receptors by ambient GABA [1]. Tonic current is typically seen during electrophysiological recordings as a continuous current, which is blocked by the GABAA receptor blockers such as GABAzine, picrotoxin and bicuculline. Because of its persistent increase in input conductance, tonic inhibition dominates over the conventional (phasic) synaptic inhibition in controlling neuronal excitability [1]. Thus, tonic inhibition plays an important role in neuronal information processing [2], and it has been implicated in epilepsy, absence seizure, sleep, memory, cognition and motor impairment [3-6].Tonic inhibition was first identified in the cerebellum, where it is particularly prominent [7]. Recently, more studies on tonic inhibition have been performed in various regions including hippocampus and thalamus [8-11]. So far, tonic inhibition has been demonstrated in dentate granule cells [9,11], thalamocortical neurons in thalamus [5], pyramidal neurons in neocortex [12] and neurons of motor cortex [13].Unlike those brain regions, Tonic inhibition in hippocampal CA1 region is somewhat controversial. It is reported to be absent in the pyramidal neurons of hippocampal CA1 and could be detected only in early development or in specific circumstances [10]. Other investigators reported tonic inhibition currents in pyramidal neuron after pre-incubating with GABA-transaminase inhibitor or GABA [3,14] to artificially enhance the ambient GABA level. These studies indicated that pyramidal neurons express high affinity extrasynaptic GABA receptors, ready to sense tonic GABA release. Similarly, Semyanov et al. could not observe tonic inhibition in pyramidal neurons both in stratum oriens and stratum radiatum unless the extracellular GABA concentration was elevated experimentally [15-17]. However, significant tonic inhibition was found in the interneurons of hippocampal CA1 region [16]. T
Presynaptic Nicotinic α7 and Non-α7 Receptors Stimulate Endogenous GABA Release from Rat Hippocampal Synaptosomes through Two Mechanisms of Action  [PDF]
Stefania Zappettini,Massimo Grilli,Federica Lagomarsino,Anna Cavallero,Ernesto Fedele,Mario Marchi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016911
Abstract: Although converging evidence has suggested that nicotinic acetylcholine receptors (nAChR) play a role in the modulation of GABA release in rat hippocampus, the specific involvement of different nAChR subtypes at presynaptic level is still a matter of debate. In the present work we investigated, using selective α7 and α4β2 nAChR agonists, the presence of different nAChR subtypes on hippocampal GABA nerve endings to assess to what extent and through which mechanisms they stimulate endogenous GABA release.
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