GABA as an inhibitory neurotransmitter in human cerebral cortex

1989 ◽  
Vol 62 (5) ◽  
pp. 1018-1027 ◽  
Author(s):  
D. A. McCormick
Keyword(s):  
Cerebral Cortex ◽  
Cortical Neurons ◽  
Epileptiform Activity ◽  
Reversal Potential ◽  
Membrane Conductance ◽  
Pyramidal Cells ◽  
Excitatory Postsynaptic Potential ◽  
Gamma Aminobutyric Acid ◽  
Human Cerebral Cortex ◽  
Inhibitory Neurotransmitter

1. The possible role of gamma-aminobutyric acid (GABA) as an inhibitory neurotransmitter in the human cerebral cortex was investigated with the use of intracellular recordings from neocortical slices maintained in vitro. 2. Electrical stimulation of afferents to presumed pyramidal cells resulted in an initial excitatory postsynaptic potential (EPSP) followed by fast and slow inhibitory postsynaptic potentials (IPSPs). The early IPSP had an average reversal potential of -68 mV, was associated with a mean 67-nS increase in membrane conductance, was reduced by the GABAA antagonist bicuculline, was sensitive to the intracellular injection of Cl-, and was mimicked by the GABAA agonist muscimol. 3. The late IPSP, in contrast, had an average reversal potential of -95 mV, was associated with a mean 12-nS increase in membrane conductance, was reduced by the GABAB antagonist phaclofen, and was mimicked by the GABAB agonist baclofen. 4. Block of the early IPSP by bicuculline or picrotoxin led to the generation of paroxysmal epileptiform activity, which could be further enhanced by reduction of the late IPSP. 5. These data strongly support the hypothesis that GABA is a major inhibitory neurotransmitter in the human cerebral cortex and that GABAergic IPSPs play an important role in controlling the excitability and responsiveness of cortical neurons.

Neurotransmitters in the cerebral cortex

1986 ◽  
Vol 65 (2) ◽  
pp. 135-153 ◽  
Author(s):  
Edward G. Jones
Keyword(s):  
Cerebral Cortex ◽  
Basal Forebrain ◽  
Cortical Neurons ◽  
Pyramidal Cells ◽  
Gamma Aminobutyric Acid ◽  
Content Type ◽  
Disease States ◽  
Afferent Fibers ◽  
Cortical Interneurons ◽  
Fine Print

✓ This article surveys the conventional neurotransmitters and modulatory neuropeptides that are found in the cerebral cortex and attempts to place them into the perspective of both intracortical circuitry and cortical disease. The distribution of these substances is related, where possible, to particular types of cortical neuron or to afferent or efferent fibers. Their physiological actions, where known, on cortical neurons are surveyed, and their potential roles in disease states such as the dementias, epilepsy, and stroke are assessed. Conventional transmitters that occur in afferent fibers to the cortex from brain-stem and basal forebrain sites are: serotonin, noradrenaline, dopamine, and acetylcholine. All of these except dopamine are distributed to all cortical areas: dopamine is distributed to frontal and cingulate areas only. The transmitter in thalamic afferent systems is unknown. Gamma aminobutyric acid (GABA) is the transmitter used by the majority of cortical interneurons and has a profound effect upon the shaping of receptive field properties. The vast majority of the known cortical peptides are found in GABAergic neurons, and the possibility exists that they may act as trophic substances for other neurons. Levels of certain neuropeptides decline in cases of dementia of cortical origin. Acetylcholine is the only other known transmitter of cortical neurons. It, too, is contained in neurons that also contain a neuropeptide. The transmitter(s) used by excitatory cortical interneurons and by the efferent pyramidal cells is unknown, but it may be glutamate or aspartate. It is possible that excitotoxins released in anoxic disease of the cortex may produce damage by acting on receptors for these or related transmitter agents.

BICUCULLINE/BACLOFEN-INSENSITIVE GABA RESPONSE IN CRUSTACEAN NEURONES IN CULTURE

1994 ◽  
Vol 191 (1) ◽  
pp. 167-193
Author(s):  
C Jackel ◽  
W Krenz ◽  
F Nagy
Keyword(s):  
Reversal Potential ◽  
Membrane Conductance ◽  
Gamma Aminobutyric Acid ◽  
Action Potential Firing ◽  
Patch Clamp Technique ◽  
Conformationally Restricted ◽  
Whole Cell Patch Clamp ◽  
Gabac Receptor ◽  
Potential Firing ◽  
Sr 95531

Neurones were dissociated from thoracic ganglia of embryonic and adult lobsters and kept in primary culture. When gamma-aminobutyric acid (GABA) was applied by pressure ejection, depolarizing or hyperpolarizing responses were produced, depending on the membrane potential. They were accompanied by an increase in membrane conductance. When they were present, action potential firing was inhibited. The pharmacological profile and ionic mechanism of GABA-evoked current were investigated under voltage-clamp with the whole-cell patch-clamp technique. The reversal potential of GABA-evoked current depended on the intracellular and extracellular Cl- concentration but not on extracellular Na+ and K+. Blockade of Ca2+ channels by Mn2+ was also without effect. The GABA-evoked current was mimicked by application of the GABAA agonists muscimol and isoguvacine with an order of potency muscimol>GABA>isoguvacine. cis-4-aminocrotonic acid (CACA), a folded and conformationally restricted GABA analogue, supposed to be diagnostic for the vertebrate GABAC receptor, also induced a bicuculline-resistant chloride current, although with a potency about 10 times lower than that of GABA. The GABA-evoked current was largely blocked by picrotoxin, but was insensitive to the GABAA antagonists bicuculline, bicuculline methiodide and SR 95531 at concentrations of up to 100 µmol l-1. Diazepam and phenobarbital did not exert modulatory effects. The GABAB antagonist phaclophen did not affect the GABA-induced current, while the GABAB agonists baclophen and 3-aminopropylphosphonic acid (3-APA) never evoked any response. Our results suggest that lobster thoracic neurones in culture express a chloride-conducting GABA-receptor channel which conforms to neither the GABAA nor the GABAB types of vertebrates but shows a pharmacology close to that of the novel GABAC receptor described in the vertebrate retina.

Characterization of synaptically mediated fast and slow inhibitory processes in piriform cortex in an in vitro slice preparation

1988 ◽  
Vol 59 (5) ◽  
pp. 1352-1376 ◽  
Author(s):  
G. F. Tseng ◽  
L. B. Haberly
Keyword(s):  
Membrane Potential ◽  
Piriform Cortex ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Membrane Depolarization ◽  
Resting Membrane Potential ◽  
Excitatory Postsynaptic Potential ◽  
Pentobarbital Sodium ◽  
Postsynaptic Potential ◽  
Conductance Increase

1. Intracellular recordings were obtained from anatomically verified layer II pyramidal cells in slices from rat piriform cortex cut perpendicular to the surface. 2. Responses to afferent and association fiber stimulation at resting membrane potential consisted of a depolarizing potential followed by a late hyperpolarizing potential (LHP). Membrane polarization by current injection revealed two components in the depolarizing potential: an initial excitatory postsynaptic potential (EPSP) followed at brief latency by an inhibitory postsynaptic potential (IPSP) that inverted with membrane depolarization and truncated the duration of the EPSP. 3. The early IPSP displayed the following characteristics suggesting mediation by gamma-aminobutyric acid (GABA) receptors linked to Cl- channels: associated conductance increase, sensitivity to increases in internal Cl- concentration, blockage by picrotoxin and bicuculline, and potentiation by pentobarbital sodium. The reversal potential was in the depolarizing direction with respect to resting membrane potential so that the inhibitory effect was exclusively via current shunting. 4. The LHP had an associated conductance increase and a reversal potential of -90 mV in normal bathing medium that shifted according to Nernst predictions for a K+ potential with changes in external K+ over the range 4.5-8 mM indicating mediation by the opening of K+ channels and ruling out an electrogenic pump origin. 5. Lack of effect of bath-applied 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) or internally applied ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) on the LHP and failure of high amplitude, direct membrane depolarization to evoke a comparable potential, argue against endogenous mediation of the LHP by a Ca2+ activated K+ conductance [gK(Ca)]. However, an apparent endogenously mediated gK(Ca) with a duration much greater than the LHP was observed in a low percent of layer II pyramidal cells. Lack of effect of 8-Br-cAMP also indicates a lack of dependence of the LHP on cAMP. 6. Other characteristics of the LHP that were demonstrated include: a lack of blockage by GABAA receptor antagonists, a probable voltage sensitivity (decrease in amplitude in the depolarizing direction), and an apparent brief onset latency (less than 10 ms) when the early IPSP was blocked by picrotoxin. The LHP was unaffected by pentobarbital sodium when the early IPSP was blocked by picrotoxin. 7. Both the LHP and early IPSP were blocked by low Ca2+/high Mg2+, consistent with disynaptic mediation.(ABSTRACT TRUNCATED AT 400 WORDS)

Possible Effects of Depolarizing GABAA Conductance on the Neuronal Input–Output Relationship: A Modeling Study

2005 ◽  
Vol 93 (6) ◽  
pp. 3504-3523 ◽  
Author(s):  
Kenji Morita ◽  
Kunichika Tsumoto ◽  
Kazuyuki Aihara
Keyword(s):  
Firing Rate ◽  
Cortical Neurons ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Resting Potential ◽  
Input Output ◽  
Wide Range ◽  
The Relationship

Recent in vitro experiments revealed that the GABAA reversal potential is about 10 mV higher than the resting potential in mature mammalian neocortical pyramidal cells; thus GABAergic inputs could have facilitatory, rather than inhibitory, effects on action potential generation under certain conditions. However, how the relationship between excitatory input conductances and the output firing rate is modulated by such depolarizing GABAergic inputs under in vivo circumstances has not yet been understood. We examine herewith the input–output relationship in a simple conductance-based model of cortical neurons with the depolarized GABAA reversal potential, and show that a tonic depolarizing GABAergic conductance up to a certain amount does not change the relationship between a tonic glutamatergic driving conductance and the output firing rate, whereas a higher GABAergic conductance prevents spike generation. When the tonic glutamatergic and GABAergic conductances are replaced by in vivo–like highly fluctuating inputs, on the other hand, the effect of depolarizing GABAergic inputs on the input–output relationship critically depends on the degree of coincidence between glutamatergic input events and GABAergic ones. Although a wide range of depolarizing GABAergic inputs hardly changes the firing rate of a neuron driven by noncoincident glutamatergic inputs, a certain range of these inputs considerably decreases the firing rate if a large number of driving glutamatergic inputs are coincident with them. These results raise the possibility that the depolarized GABAA reversal potential is not a paradoxical mystery, but is instead a sophisticated device for discriminative firing rate modulation.

Ammonia does not selectively block IPSPs in rat hippocampal pyramidal cells

1983 ◽  
Vol 49 (6) ◽  
pp. 1381-1391 ◽  
Author(s):  
B. E. Alger ◽  
R. A. Nicoll
Keyword(s):  
Reversal Potential ◽  
Pyramidal Cells ◽  
Gamma Aminobutyric Acid ◽  
Postsynaptic Potentials ◽  
Calcium Dependent ◽  
Nonspecific Effects ◽  
Chloride Pump ◽  
High Concentrations ◽  
Conductance Increase ◽  
Potassium Response

Intracellular recordings from CA1 pyramidal cells in the rat hippocampal slice preparation have been used to study the action of ammonia on inhibitory postsynaptic potentials (IPSPs). Concentrations of ammonia less than 2 mM had little effect on IPSPs or the action of iontophoretically applied gamma-aminobutyric acid (GABA). This concentration has been reported to be fully effective in blocking hyperpolarizing IPSPs in spinal cord and neocortex. Concentrations above 2 mM did cause a depolarizing shift in the IPSP and GABA reversal potentials, but this effect was accompanied by several generalized effects. The conductance increase during the IPSP but not during the GABA response was depressed, indicating that ammonia has a presynaptic depressant effect on the IPSP. Ammonia also depressed excitatory postsynaptic potentials (EPSPs), presynaptic fiber potentials, and pyramidal cell population spikes. In addition, the calcium-dependent potassium response elicited by depolarizing current pulses was depressed. This depression was due, in part, to a depolarizing shift in the reversal potential for this response. Responses recorded with potassium-sensitive microelectrodes indicate that ammonia releases potassium into the extracellular space. The possibility is discussed that the shifts in IPSP reversal potential seen with high concentrations of ammonia are a consequence of generalized nonspecific effects. We conclude that the relative insensitivity of hippocampal IPSPs to blockade by ammonia suggests that a mechanism fundamentally unlike an ammonia-sensitive chloride pump must maintain the hippocampal IPSP gradient.

KRIT1/Cerebral Cavernous Malformation 1 Protein Localizes to Vascular Endothelium, Astrocytes, and Pyramidal Cells of the Adult Human Cerebral Cortex

Neurosurgery ◽  
2004 ◽  
Vol 54 (4) ◽  
pp. 943-949 ◽  
Author(s):  
Ozlem Guzeloglu-Kayisli ◽  
Nduka M. Amankulor ◽  
Jennifer Voorhees ◽  
Guven Luleci ◽  
Richard P. Lifton ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Vascular Endothelium ◽  
Cavernous Malformation ◽  
Pyramidal Cells ◽  
Cerebral Cavernous Malformation ◽  
Human Cerebral Cortex ◽  
Adult Human

Role of norepinephrine in seizurelike activity of hippocampal pyramidal cells maintained in vitro: alteration by 6-hydroxydopamine lesions of norepinephrine-containing systems

1983 ◽  
Vol 61 (8) ◽  
pp. 841-846 ◽  
Author(s):  
I. Mody ◽  
P. Leung ◽  
J. J. Miller
Keyword(s):  
Epileptiform Activity ◽  
Pyramidal Cells ◽  
Population Spike ◽  
Stratum Radiatum ◽  
Excitatory Postsynaptic Potential ◽  
Ca1 Pyramidal Cells ◽  
Ca1 Region ◽  
Population Spike Amplitude ◽  
6 Hydroxydopamine

Perfusion of 50 μM norepinephrine (NE) produced a marked, reversible decrease (range 20–28%) of the extracellular population spike and excitatory postsynaptic potential (EPSP) responses of the CA1 region evoked by stratum radiatum stimulation in the rat hippocampal slice preparation. The effects of NE were dramatically altered in slices obtained from animals which were previously treated with intracerebral or intraventricular injections of 6-hydroxydopamine (6-OHDA) to destroy forebrain catecholamine systems. In the latter preparations NE produced a reduction in the inhibition of the EPSP (50%), enhancement of the population spike amplitude, and multiple spike discharges characteristic of ongoing epileptiform activity. The reversal of NE-induced inhibition and the generation of seizurelike activity in 6-OHDA-treated animals suggests that NE may, in part, act upon interneurons to produce a disinhibition of CA1 pyramidal cells.

scholarly journals Maturation of the Human Cerebral Cortex During Adolescence: Myelin or Dendritic Arbor?

2018 ◽  
Vol 29 (8) ◽  
pp. 3351-3362 ◽  
Author(s):  
Y Patel ◽  
J Shin ◽  
P A Gowland ◽  
Z Pausova ◽  
T Paus ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Pyramidal Cells ◽  
In Vivo Studies ◽  
Ependymal Cells ◽  
Specific Gene ◽  
Magnetization Transfer Ratio ◽  
Dendritic Arbor ◽  
Human Cerebral Cortex ◽  
Regional Variations ◽  
Age Related

Abstract Previous in vivo studies revealed robust age-related variations in structural properties of the human cerebral cortex during adolescence. Neurobiology underlying these maturational phenomena is largely unknown. Here we employ a virtual-histology approach to gain insights into processes associated with inter-regional variations in cortical microstructure and its maturation, as indexed by magnetization transfer ratio (MTR). Inter-regional variations in MTR correlate with inter-regional variations in expression of genes specific to pyramidal cells (CA1) and ependymal cells; enrichment analyses indicate involvement of these genes in dendritic growth. On the other hand, inter-regional variations in the change of MTR during adolescence correlate with inter-regional profiles of oligodendrocyte-specific gene expression. Complemented by a quantitative hypothetical model of the contribution of surfaces associated with dendritic arbor (1631 m2) and myelin (48 m2), these findings suggest that MTR signals are driven mainly by macromolecules associated with dendritic arbor while maturational changes in the MTR signal are associated with myelination.

scholarly journals Diazepam Accelerates GABAAR Synaptic Exchange and Alters Intracellular Trafficking

2019 ◽  
Author(s):  
Joshua M. Lorenz-Guertin ◽  
Matthew J. Bambino ◽  
Sabyasachi Das ◽  
Susan T. Weintraub ◽  
Tija C. Jacob
Keyword(s):  
Cortical Neurons ◽  
Fluorescent Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Adult Brain ◽  
Scaffolding Protein ◽  
Gamma Aminobutyric Acid ◽  
Inhibitory Neurotransmitter

Despite 50+ years of clinical use as anxiolytics, anti-convulsants, and sedative/hypnotic agents, the mechanisms underlying benzodiazepine (BZD) tolerance are poorly understood. BZDs potentiate the actions of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABAARs). Here we define key molecular events impacting γ2 GABAAR and the inhibitory synapse gephyrin scaffold following initial sustained BZD exposure in vitro and in vivo. Using immunofluorescence and biochemical experiments, we found that cultured cortical neurons treated with the classical BZD, diazepam (DZP), presented no substantial change in surface or synaptic levels of γ2-GABAARs. In contrast, both γ2 and the postsynaptic scaffolding protein gephyrin showed diminished total protein levels following a single DZP treatment in vitro and in mouse cortical tissue. We further identified DZP treatment enhanced phosphorylation of gephyrin Ser270 and increased generation of gephyrin cleavage products. Selective immunoprecipitation of γ2 from cultured neurons revealed enhanced ubiquitination of this subunit following DZP exposure. To assess novel trafficking responses induced by DZP, we employed a γ2 subunit containing an N terminal fluorogen-activating peptide (FAP) and pH-sensitive green fluorescent protein (γ2pHFAP). Live-imaging experiments using γ2pHFAP GABAAR expressing neurons identified enhanced lysosomal targeting of surface GABAARs and increased overall accumulation in vesicular compartments in response to DZP. Using fluorescence resonance energy transfer (FRET) measurements between γ2 and γ2 subunits within a GABAAR in neurons, we identified reductions in synaptic clusters of this subpopulation of surface BZD sensitive receptor. Moreover, we found DZP simultaneously enhanced synaptic exchange of both γ2-GABAARs and gephyrin using fluorescence recovery after photobleaching (FRAP) techniques. Finally we provide the first proteomic analysis of the BZD sensitive GABAAR interactome in DZP vs. vehicle treated mice. Collectively, our results indicate DZP exposure elicits down-regulation of gephyrin scaffolding and BZD sensitive GABAAR synaptic availability via multiple dynamic trafficking processes.

Role of HCO3- ions in depolarizing GABAA receptor-mediated responses in pyramidal cells of rat hippocampus

1993 ◽  
Vol 69 (5) ◽  
pp. 1541-1555 ◽  
Author(s):  
L. M. Grover ◽  
N. A. Lambert ◽  
P. A. Schwartzkroin ◽  
T. J. Teyler
Keyword(s):  
Gabaa Receptor ◽  
Gabab Receptor ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Gamma Aminobutyric Acid ◽  
Free Medium ◽  
Postsynaptic Potentials ◽  
Ca1 Pyramidal Cells ◽  
Ionic Basis

1. Activation of GABAA receptors can produce both hyperpolarizing and depolarizing responses in CA1 pyramidal cells. The hyperpolarizing response is mediated by a Cl- conductance, but the ionic basis of the depolarizing response is not clear. We compared the GABAA receptor-mediated depolarizations induced by synaptically released gamma-aminobutyric acid [GABA; depolarizing inhibitory postsynaptic potentials (dIPSPs)] with those produced by exogenous GABA (depolarizing GABA responses). Short trains of high-frequency (200 Hz) stimuli were used to generate dIPSPs. We found that dIPSPs generated by trains of stimuli and depolarizing responses to exogenous GABA were accompanied by a conductance increase and had a similar reversal potential, indicating a similar ionic basis for both responses. 2. We wished to determine whether an HCO3- current contributed to the GABAA-mediated depolarizations. We found that dIPSPs and depolarizing GABA responses were sensitive to perfusion with HCO3(-)-free medium. Interpretation of these data was complicated by the mixed nature of the responses: dIPSPs were invariably accompanied by conventional, Cl(-)-mediated fast hyperpolarizing IPSPs (fIPSPs), and response to exogenous GABA usually consisted of biphasic hyperpolarizing and depolarizing responses. However, it was sometimes possible to elicit responses to GABA that appeared purely depolarizing (monophasic depolarizing GABA responses). 3. We analyzed monophasic depolarizing GABA responses and found no change in reversal potential when slices were perfused with HCO(3-)-free medium. We also made whole-cell recordings from CA1 pyramidal cells, attempting to reduce [HCO3-]i, and compared the reversal potential for monophasic depolarizing GABA responses with similar responses recorded with fine intracellular microelectrodes. We found no difference in reversal potential. We also examined effects of the carbonic anhydrase inhibitor acetazolamide (ACTZ) on depolarizing GABA responses. ACTZ reduced these responses but did not change their reversal potential. 4. Effects of HCO(3-)-free medium were not specific to GABAA receptor-mediated responses. GABAB receptor-mediated slow IPSPs (sIPSPs) were also reduced, as were excitatory postsynaptic potentials (EPSPs). Analyses of field potentials and spontaneous fIPSPs suggested a decrease in presynaptic excitability during perfusion with HCO(3-)-free medium. In addition, pyramidal cells showed decreased input resistance when perfused with HCO(3-)-free medium. 5. The sensitivity of GABAA receptor-mediated depolarizations to HCO(3-)-free medium can be explained by a decrease in presynaptic excitability and an increased resting conductance in postsynaptic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

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