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J J Hablitz

Publications and source records attributed to J J Hablitz.

At least 37 records · Page 2Linked to original sources
PubMed1998

AMPA receptor-mediated EPSCs in rat neocortical layer II/III interneurons have rapid kinetics.

The properties of spontaneous and miniature (m) AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) were studied in rat neocortical layer II/III fast spiking interneurons. Under optimal recording conditions, averaged mEPSCs had a 10-90% rise time of about 0.3 ms. The decay of averaged mEPSCs was double exponential with time constants of about 1 and 4 ms. Kinetics were observed to slow as series resistance increased. The amplitudes of mEPSCs were much smaller at +50 mV than at -50 mV indicating that the currents were inwardly rectifying. These results suggest that synaptic AMPA receptors on neocortical inhibitory interneurons have a deactivation time constant less than 1 ms which largely determines the decay of the synaptic currents. The receptors appear to lack GluR-2 subunits and may be Ca2+ permeable.

Animals↗
PubMed1998

Excitability changes in freeze-induced neocortical microgyria.

A freezing probe was placed on the skull of postnatal day (PN) 1 rats to induce formation of a cerebrocortical microsulcus. Experimental studies were performed on PN days 21-24. At that time point, Nissl-stained sections revealed the presence of a microsulcus similar to that described in human dysplastic cortex. Immunocytochemical staining for parvalbumin, calretinin and calbindin indicated a significant decrease in the number of immunoreactive neurons within the microsulcus and non-significant decreases in regions adjacent to the microsulcus. Staining for the glial markers GFAP and vimentin was increased near the microsulcus. Using in vitro brain slices, recordings were made in cortex adjacent to the microsulcus. Epileptiform activity was observed in response to electrical stimulation near the microsulcus. Analysis of the voltage dependence of evoked epileptiform discharges suggested the presence of an inhibitory component. As previously observed in non-lesioned animals, bath application of 4-aminopyridine induced bicuculline-sensitive spontaneous burst discharges in the presence of excitatory amino acid antagonists. These results suggest that cortical freeze lesions associated with abnormal neuronal migration produce a chronic hyperexcitable state. The findings are consistent with a mechanism involving an alteration, not loss, of inhibition in this model.

2-Amino-5-phosphonovalerate↗
PubMed1998

Activation of group I mGluRs increases spontaneous IPSC frequency in rat frontal cortex.

The effect of metabotropic glutamate receptor (mGluR) activation on inhibitory synaptic transmission was examined by using whole cell patch-clamp recordings. Spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs) were recorded from visually identified layer II/III pyramidal neurons in rat neocortex in vitro. Excitatory postsynaptic currents (EPSCs) were blocked by using bath application of 20 microM D(-)2-amino-5-phosphonovaleric acid and 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione. In the presence of 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (30-100 microM), Lp4-quisqualate (5 microM), and the group I selective mGluR agonist (S)-3,5-dihydroxyphenylglycine (100 microM), the frequency of sIPSCs was increased. Decay kinetics of sIPSCs were unaffected. No enhancement of mIPSCs was observed. Bath application of group II (2S,3S,4S-alpha-carboxycyclopropyl-glycine; 5 microM) and group III selective mGluR agonists (L-2-amino-4-phosphonobutyric acid; 100 microM) had no detectable effects on the frequency or amplitude of sIPSCs. These findings indicate that activation of group I mGluRs (mGluR1 and/or mGluR5) enhances gamma-aminobutyric acid-mediated synaptic inhibition in layer II/III pyramidal neurons in neocortex. The lack of effect on mIPSCs suggests a presynaptic action via excitation of inhibitory interneurons.

Amino Acids, Dicarboxylic↗
PubMed1998

Zinc and zolpidem modulate mIPSCs in rat neocortical pyramidal neurons.

Pharmacological modulation of gamma-aminobutyric acid-A (GABAA) receptors can provide important information on the types of subunits composing these receptors. In recombinant studies, zinc more potently inhibits alphabeta subunits compared with the alphabetagamma combination, whereas modulation by nanomolar concentrations of the benzodiazepine type 1-selective agonist zolpidem is conferred by the alpha1betagamma2 subunit combination. We examined four properties of miniature inhibitory postsynaptic currents (mIPSCs) from identified necortical pyramidal cells in rat brain slices: decay time constant, peak amplitude, rate of rise, and interevent interval. Exposure to 50 microM zinc reduced the decay time constant, peak amplitude, and rate of rise with no effect on interevent interval. Zolpidem enhanced mIPSCs in a concentration-dependent manner. Both 20 and 100 nM zolpidem increased the decay time constants of mIPSCs. In some cells, both peak amplitude and rate of rise were also enhanced. All cells treated with zinc were also responsive to zolpidem. These results show that neocortical pyramidal cells have a population of GABAA receptors sensitive to both zinc and zolpidem.

Animals↗
PubMed1997

Rapid kinetics and inward rectification of miniature EPSCs in layer I neurons of rat neocortex.

With the use of the whole cell patch-clamp technique combined with visualization of neurons in brain slices, we studied the properties of miniature excitatory postsynaptic currents (mEPSCs) in rat neocortical layer I neurons. At holding potentials (-50 to -70 mV) near the resting membrane potential (RMP), mEPSCs had amplitudes of 5-100 pA and were mediated mostly by alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptors. Amplitude histograms were skewed toward large events. An N-methyl-D-aspartate (NMDA) component was revealed by depolarization to -30 mV or by the use of a Mg2+-free bathing solution. At RMP, averaged AMPA mEPSCs had a 10-90% rise time of approximately 0.3 ms (uncorrected for instrument filtering). The decay of averaged mEPSCs was best fit by double-exponential functions in most cases. The fast, dominating component had a decay time constant of approximately 1.2 ms and comprised approximately 80% of the total amplitude. A small slow component had a decay time constant of approximately 4 ms. Positive correlations were found between rise and decay times of both individual and averaged mEPSCs, indicative of dendritic filtering. Some large-amplitude mEPSCs and spontaneous EPSCs (recorded in the absence of tetrodotoxin) had slower kinetics, suggesting a role of asynchronous transmitter release in shaping EPSCs. The amplitudes of mEPSCs were much smaller at +60 mV than at -60 mV, indicating that synaptic AMPA-receptor-mediated currents were inwardly rectifying. These results suggest that neocortical layer I neurons receive both NMDA- and AMPA-receptor-mediated synaptic inputs. The rapid decay of EPSCs appears to be largely determined by AMPA receptor deactivation. The observed rectification of synaptic responses suggests that synaptic AMPA receptors in layer I neurons may lack GluR-2 subunits and may be Ca2+ permeable.

Animals↗
PubMed1997

Metabotropic glutamate receptor enhancement of spontaneous IPSCs in neocortical interneurons.

Metabotropic glutamate receptor enhancement of spontaneous IPSCs in neocortical interneurons. J. Neurophysiol. 78: 2287-2295, 1997. Using neocortical layer I neurons as a model for GABAergic interneurons, we have studied gamma-aminobutyric acid-A (GABAA) receptor-mediated spontaneous inhibitory postsynaptic currents (IPSCs) and modulation by metabotropic glutamate receptors (mGluRs). In the presence of 0.5 mu M tetrodotoxin (TTX) and ionotropic glutamate receptor antagonists and under symmetrical Cl- conditions, the mean amplitude of miniature IPSCs (mIPSCs) was approximately 50 pA at a holding potential of -70 mV with individual events ranging from 10 to 400 pA. Averaged mIPSCs had a 10-90% rise time of approximately 0.6 ms. The decay was double exponential. The fast component had a time constant of approximately 4 ms and comprised approximately 40% of the total amplitude. The slow component had a time constant of approximately 22 ms. The frequency of spontaneous IPSCs (sIPSCs), recorded in the absence of TTX, was increased by bath application of the mGluR agonist 1S,3R-1-aminocyclopentane-1, 3-dicarboxylic acid (ACPD; 10-100 mu M) or the group I mGluR selective agonist quisqualic acid (Quis; 0.5-1 mu M). Under identical conditions, mIPSCs were not affected. The kinetics of sIPSCs and mIPSCs were not altered by ACPD or Quis. Quis (1 mu M) induced an inward current of approximately 70 pA at a holding potential of -70 mV, whereas ACPD (40-200 mu M) induced a smaller inward current. This current was linear over the voltage range -70 to +30 mV and reversed polarity near 0 mV. In current-clamp recordings, both Quis and ACPD induced a depolarization and action potential firing in layer I and deeper layer interneurons. We conclude that neocortical layer I neurons receive GABAA receptor-mediated inhibitory synaptic inputs. Activation of mGluRs, possibly mGluR1 and/or mGluR5, causes an enhancement of inhibitory synaptic transmission by directly depolarizing corticalGABAergic interneurons through the opening of nonselective cation channels.

Action Potentials↗
PubMed1996

Morphological properties of intracellularly labeled layer I neurons in rat neocortex.

The morphology of neurons in layer I of rat neocortex, including Cajal-Retzius (CR) cells, was studied by using intracellular biocytin staining in brain slices obtained from rats during the first 22 postnatal days. Within the first postnatal week, horizontal bipolar neurons or CR cells were prominent in layer I. Typically, CR cells had one main dendrite and one axon originating from opposite poles of the somata. Even though the main dendrites and axons could be quite long, complex dendritic or axonal arbors were not observed. Starting around postnatal day 6 (PN 6), CR cells were less frequently observed. From PN 10 to PN 21, nonpyramidal neurons with diverse morphologies became the main neuronal component in layer I. The somata of layer I nonpyramidal neurons were quite variable in size and shape. Dendrites were smooth or sparsely spiny, and the dendritic trees were mainly restricted to layer I, covering an area with a diameter of about 200 microns. Axon collaterals of these cells formed elaborate arbors with diameters of around 700 microns in layer I and extending, in many cases, to layer II/III and even layer IV. This extensive axonal plexus provides a rich anatomical base on which layer I neurons, functioning as local circuit elements, may interact with each other and with neurons in other layers.

Animals↗
PubMed1996

Postnatal development of membrane properties of layer I neurons in rat neocortex.

Using whole-cell patch-clamp techniques in brain slices, we studied the postnatal development of electrophysiological properties of rat neocortical layer I neurons during the first three weeks of postnatal life. Neurons, including Cajal-Retzius cells, were visualized under Nomarski optics before recording. In the first postnatal week, all layer I neurons, including Cajal-Retzius cells, had low resting membrane potentials (-40 to -55 mV), high input resistances (1-5 G omega), and long membrane time constants (80-130 msec). Action potentials (APs) of layer I neurons early in postnatal development were lower in amplitude and longer in duration. The threshold for APs also was more depolarized than in older neurons. A medium after-hyperpolarization already was present at postnatal day 0 (PN0), but fast afterhyperpolarizations were not seen until PN10. At all postnatal ages, layer I neurons were capable of repetitive firing, displayed little or no frequency adaptation, and did not display slow afterhyperpolarizations. Early in development, layer I neurons had a prominent hyperpolarization-activation depolarizing sag that decreased with age. These results suggest that the membrane properties of rat neocortical layer I neurons mature rapidly during the first two postnatal weeks. Cajal-Retzius cells had electrical properties similar to other layer I neurons and did not show an earlier maturation of membrane properties.

Action Potentials↗
PubMed1996

G-protein activation by metabotropic glutamate receptors reduces spike frequency adaptation in neocortical neurons.

Intracellular recordings were obtained from neocortical brain slices of adult rats maintained in vitro. The effect of metabotropic glutamate receptor activation on spike frequency adaptation in regular spiking layer II and III neurons was determined. Putative metabotropic glutamate receptor agonists and antagonists, as well as inhibitors of intracellular signaling systems, were tested. Activation of metabotropic glutamate receptors by bath applied (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD; 50-200 microM) reduced the first interspike interval and increased action potential frequency at all current intensities. This effect was not blocked by ionotropic glutamate receptor antagonists. Under these recording conditions, quisqualate (1-10 microM) similarly reduced spike frequency adaptation. Neither 1R,3S-ACPD, L-2-carboxycyclopropylglycine-I nor the putative presynaptic metabotropic glutamate receptor agonist, L-2-amino-4-phosphonobutyrate, mimicked the effects of 1S,3R-ACPD or quisqualate. Bath application of the putative metabotropic glutamate receptor antagonist, alpha-methyl-4-carboxyphenylglycine, competitively antagonized the excitatory actions of 1S,3R-ACPD. Another putative antagonist, L-2-amino-3-phosphonopropionate, failed to antagonize the reduction in spike frequency adaptation. Intracellular injection of guanosine-5'-O-(2-thiodiphosphate), a non-hydrolysable analog of GTP, inhibited the postsynaptic metabotropic glutamate receptor-mediated effects. However, the depression of synaptic transmission by 1S,3R-ACPD was not antagonized by this compound. The decrease in spike frequency adaptation by 1S,3R-ACPD was not prevented by prior exposure to the non-specific protein kinase inhibitors H-7 or H-8 (10 microM), the protein kinase A inhibitor H-89 (0.25 microM) or the protein kinase C inhibitor staurosporine (0.10 microM). These data suggest that the metabotropic glutamate receptor-mediated reduction in spike adaptation requires the activation of specific G-protein-coupled metabotropic glutamate receptor subtypes located on postsynaptic sites. The increase in neuronal excitability observed in the adult neocortex may be mediated either by an unidentified G-protein-coupled second messenger or via a membrane-delimited G-protein action.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1996

Layer I neurons of rat neocortex. I. Action potential and repetitive firing properties.

1. Whole cell patch-clamp techniques, combined with direct visualization of neurons, were used to study action potential (AP) and repetitive firing properties of layer I neurons in slices of rat neocortex. 2. Layer I neurons had resting membrane potentials (RMP) of -59.8 +/- 4.7 mV (mean +/- SD) and input resistances (RN) of 592 +/- 284 M Omega. Layer II/III pyramidal neurons had RMPs and RNs of -61.5 +/- 5.6 mV and 320 +/- 113 M omega, respectively. A double exponential function was needed to describe the charging curves of both neuron types. In layer I neurons, tau(0) was 45 +/- 22 ms and tau(1) was 5 +/- 3.3 ms whereas in layer II/III pyramidal neurons, tau(0) was 41 +/- 11 ms and tau(1) was 3 +/- 2.6 ms. Estimates of specific membrane resistance (Rm) for layer I and layer II/III cells were 45 +/- 22 and 41 +/- 11 k omega cm2, respectively (Cm was assumed to be 1 microF/cm2). 3. AP threshold was -41 +/- 2 mV in layer I neurons. Spike amplitudes, measured from threshold to peak, were 90.6 +/- 7.7 mV. AP durations, measured both at the base and half maximal amplitude, were 2.5 +/- 0.4 and 1.1 +/- 0.2 ms, respectively. AP 10-90% rise and repolarization times were 0.6 +/- 0.1 and 1.1 +/- 0.2 ms, respectively. In layer II/III pyramidal neurons, AP threshold was -41 +/- 2.5 mV and spike amplitude was 97 +/- 9.7 mV. AP duration at base and half maximal amplitude was 5.4 +/- 1.1 ms and 1.8 +/- 0.2 ms, respectively. AP 10-90% rise and decay times were 0.6 +/- 0.1 ms and 2.8 +/- 0.6 ms, respectively. 4. Layer I neurons were fast spiking cells that showed little frequency adaptation, a large fast afterhyperpolarization (fAHP), and no slow afterhyperpolarization (sAHP). Some cells had a medium afterhyperpolarization (mAHP) and a slow afterdepolarization (sADP). All pyramidal cells in layer II/III and "atypical" pyramidal neurons in upper layer II showed regular spiking behavior, prominent frequency adaptation, and marked sAHPs. 5. In both layer I neurons and layer II/III pyramidal neurons, changes in membrane potential did not greatly alter AP properties. The duration of APs evoked from -50 to -60 mV was only slightly longer, from -80 to -90 mV. The latency to first spike also was not solely dependent on membrane potential. 6. During repetitive firing, APs broadened in both layer I neurons and layer II/III pyramidal neurons. This was most prominent in pyramidal cells. Broadening was dependent on spike frequency and appeared to result from partial inactivation of both outward potassium and inward sodium currents. 7. In layer I neurons, removing Ca2+ from the bathing solution slightly prolonged spike duration and modestly increased AP firing frequency. These results indicate minimal involvement of Ca2+-dependent K+ currents in AP repolarization. fAHPs were reduced whereas sADPs were abolished. In layer II/III pyramidal neurons, removing Ca2+ reduced or blocked mAHPs and sAHPs and decreased or abolished frequency adaptation. 8. Low concentrations (50 microM) of 4-aminopyridine (4-AP) prolonged APs and induced burst-like firing in layer I neurons. In the presence of 4-AP, the spiking behavior of layer I neurons resembled that of regular spiking layer II/III pyramidal cells. At high concentrations (4 mM), 4-AP could induce a delayed depolarization (DD) after each spike in layer I neurons and in a minority of pyramidal neurons. 9. All layer I neurons had a prominent fAHP that was absent or very small in layer II/III pyramidal neurons. fAHP amplitude was inversely related to AP duration. The reduction of fAHPs by 4-AP or during repetitive firing was accompanied by AP prolongation, suggesting that the current underlying fAHP played an essential role in AP repolarization. The fAHP of layer I neurons could be effectively blocked by 4-AP but only slightly reduced by removing Ca2+ from bathing solution, indicating that the fAHP was mediated primarily by a voltage-dependent transient outward current.(ABSTRACT TRUNCATED)

Action Potentials↗
PubMed1996

Layer I neurons of the rat neocortex. II. Voltage-dependent outward currents.

1. Whole cell patch-clamp techniques, combined with direct visualization of neurons, were used to study voltage-dependent potassium currents in layer 1 neurons and layer II/III pyramidal cells. 2. In the presence of tetrodotoxin, step depolarizations evoked an outward current. This current had a complex waveform and appeared to be a composite of early and late components. The early peak of the composite K+ outward current was larger in layer I neurons. 3. In both layer I and pyramidal cells, the composite outward K+ current could be separated into two components based on kinetic and pharmacological properties. The early component was termed I(A) because it was a transient outward current activating rapidly and then decaying. I(A) was more sensitive to blocking by 4-aminopyridine (4-AP) than tetraethylammonium (TEA). The second component, termed the delayed rectifier or I(DR), activated relatively slowly and did not decay significantly during a 200-ms test pulse. I(DR) was insensitive to blocking by 4-AP at concentrations up to 4 mM and blocked by > 60% by 40-60 mM TEA. 4. I(A) kinetics were examined in the presence of 40-60 mM TEA. Under these conditions, I(A) began to activate between -40 and -30 mV. Half-maximal activation occurred around 0 mV. In both layer I and pyramidal cells, the half-inactivation potential (Vh-inact) was around or more positive than -50 mV. At -60 mV, > 70% of I(A) conductance was available. I(A) decayed along a single exponential time course with a time constant of approximately 15 ms. This decay showed little voltage dependence. 5. In both layer I and pyramidal cells, I(DR) was studied in the presence of 4 mM 4-AP to block I(A) and in saline containing 0.2 mM Ca2+ and 3.6 mM Mg2+ to reduce contributions from Ca2+-dependent K+ currents. Under these conditions, I(DR) began to activate at -35 to -25 mV with Vh-act of 3.6 +/- 4.5 mV (mean +/- SD). The 10-90% rise time of I(DR) was 15 ms at 30 mV. At 2.2 ms after the onset of the command potential to +30 mV, I(DR) could reach a significant amplitude (approximately 1.5 nA in layer I neurons and 2.2 nA in pyramidal cells depending on the cell size). When long test pulses (> or = 1,000 ms) were used, a decay time constant approximately 800 ms at +40 mV was observed. In both layer I and pyramidal cells, steady state inactivation of I(DR) was minimal. 6. These results indicate that I(A) and I(DR) are the two major hyperpolarizing currents in layer I and pyramidal cells. The kinetics and pharmacological properties of I(A) and I(DR) were not significantly different in fast-spiking layer I neurons and regular-spiking layer II/III pyramidal cells. The relatively positive activation threshold (more than or equal to -40 mV) of both I(A) and I(DR) suggest that they do not play a role in neuronal behavior below action potential (AP) threshold and that their properties are more suitable to repolarize AP. The greater density of I(A) in layer I neurons appears responsible for fast spike generation.

Action Potentials↗
PubMed1995

N-methyl-D-aspartate receptor-mediated calcium accumulation in neocortical neurons.

Calcium imaging and patch-clamp recording techniques were used to investigate the relationship between membrane properties and intracellular calcium changes in response to the excitatory amino acid neurotransmitter glutamate. Application of glutamate to cultured neocortical neurons produced concentration-dependent increases in intracellular calcium, membrane depolarization and transmembrane current. At a low concentration (3 microM), glutamate induced only a small depolarization (< 10 mV), yet produced a substantial increase in intracellular calcium. The calcium increase was observed in the presence of extracellular magnesium, was dependent on extracellular calcium, was blocked by an N-methyl-D-aspartate receptor antagonist, and was not affected by manipulation of intracellular calcium stores. This low concentration of glutamate also induced membrane currents that exhibited an N-methyl-D-aspartate-like unconventional voltage dependence. When glutamate was increased to a concentration known to produce excitotoxicity (500 microM), large depolarizations and membrane currents were induced, which rapidly reversed following prolonged glutamate applications. Changes in intracellular calcium in response to 500 microM glutamate had both voltage-sensitive and -insensitive components, and consistently remained elevated following removal of glutamate. These results indicate that low concentrations of glutamate can preferentially activate N-methyl-D-aspartate receptors, leading to increases in intracellular calcium. Functionally this may be involved in N-methyl-D-aspartate receptor responses to ambient extracellular glutamate. In addition, N-methyl-D-aspartate receptor-mediated calcium influx and subsequent depolarization induced by high glutamate concentrations can produce alterations in intracellular calcium homeostasis, which may play an important role in excitotoxicity.

Animals↗
PubMed1995

Modulation of epileptiform activity by metabotropic glutamate receptors in immature rat neocortex.

1. Intracellular and extracellular recordings were obtained from neocortical brain slices of immature rats (postnatal days 9-16) maintained in vitro. Spontaneous and evoked epileptiform discharges (termed paroxysmal depolarizing shifts or PDSs) were recorded from upper cortical laminae (layers II-III) after exposure to the gamma-aminobuturic acid-A receptor antagonist, bicuculline methiodide. The effects of mGluR activation on PDS duration, spontaneous frequency, and threshold for evoking a PDS were determined. Putative mGluR agonists and antagonists also were tested. 2. Bath application of the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD, 50-200 mM) elicited biphasic, time-dependent effects on evoked and spontaneous epileptiform discharges. At times early in drug wash-in, ACPD increased PDS duration and spontaneous PDS frequency. In > 60% of the slices, the spontaneous PDSs became regular. Subsequently, ACPD reduced PDS duration and increased the stimulus threshold for evoking a PDS, suggesting that the actions of ACPD were dose dependent. 3. Investigation of the concentration-dependence revealed that sustained low ACPD concentrations (5 microM) elicited only facilitatory actions, whereas higher concentrations were suppressive. These observations suggest the activation of different mGluR subtypes, which may be localized differentially at pre- and postsynaptic sites. 4. Bath application of the mGluR agonists, L-2-amino-4-phosphonobutyrate or (2S,3S,4S)-alpha-(carboxycyclopropyl) glycine, produced only suppressive effects on epileptiform activity in the immature neocortex. L-2-amino-3-phosphonopropionate was an ineffective antagonist of ACPD-mediated modulation of epileptiform activity. Application of the putative antagonist, alpha-methyl-4-carboxyphenylglycine (MCPG), failed to antagonize the biphasic actions of ACPD. MCPG had suppressive effects of epileptiform activity, suggesting activation of mGluRs by endogenous agonists. 5. Simultaneous recordings from deeper and upper cortical layers indicated that the initial negativity of both evoked and spontaneous PDSs began in deeper cortical layers under control conditions and in the presence of ACPD. Intracellular records from neurons in deeper layers displayed two distinct patterns of activity during mGluR activation. Most deep layer neurons received a barrage of excitatory postsynaptic potentials before a spontaneous PDS during ACPD application. A small population of neurons depolarized and entered a tonically firing mode, which was interrupted by spontaneous PDSs. Different neuronal populations, possible expressing different mGluR subtypes or coupling mechanisms, may play integral roles in the induction and generation of epileptiform activities. 6. Thapsigargin or dantrolene, agents thought to block release of Ca2+ from intracellular stores, were both applied for periods < or = min.(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

Developmental changes in the voltage-dependence of neocortical NMDA responses.

A change in the response of neocortical neurons to N-methyl-D-aspartate (NMDA) was observed during the first 2 weeks of postnatal development. When NMDA was bath applied, the membrane current-voltage relationship recorded in neurons from postnatal day (PN) 3-5 rats displayed a region of decreased inward current at hyperpolarized membrane potentials. By PN 9-14, the net inward current at hyperpolarized potentials was significantly less than that recorded in PN 3-5 neurons. These results indicate that a developmental increase in the voltage-dependence of NMDA responses exists, which may be due to changes in magnesium sensitivity of the NMDA receptor.

Animals↗
PubMed1994

Metabotropic glutamate receptor activation decreases epileptiform activity in rat neocortex.

Intracellular and extracellular recordings were obtained from layers II-III of slices of adult rat neocortex maintained in vitro. Excitatory postsynaptic potentials (EPSPs) and epileptiform discharges (paroxysmal depolarizing shifts, PDSs) were evoked in the presence of bicuculline methiodide. Responses were monitored before, during, and after bath application of the putative metabotropic glutamate receptor agonists, 1S, 3R-ACPD and L-AP4. Peak EPSP amplitude and both PDS amplitude and duration were reduced during 1S,3R-ACPD application. Area measurements indicate that PDSs were reduced to 51.7 +/- 19.9% of control. Stimulus threshold for evoking a PDS was increased in the presence of 1S,3R-ACPD or L-AP4. Pretreatment of slices with 1S.3R-ACPD did not prevent the generation of epileptiform events when bicuculline subsequently was applied. These results indicate that mGluR activation by 1S,3R-ACPD has significant suppressive effects on evoked epileptiform activity in the adult rat neocortex in vitro.

Aminobutyrates↗
PubMed1994

Paired-pulse facilitation in the dentate gyrus: a patch-clamp study in rat hippocampus in vitro.

1. Whole-cell patch-clamp recordings were used to study paired-pulse facilitation (PPF) of the lateral perforant path input to the dentate gyrus in thin hippocampal slices. 2. Orthodromic stimulation of the lateral perforant pathway evoked a excitatory postsynaptic current (EPSC) with a latency of 3.3 +/- 0.1 ms (mean +/- SE) that fluctuated in amplitude. The EPSC had a rise time (10-90%) of 2.79 +/- 0.06 ms (n = 35) and decayed with a single exponential time course with a time-constant of 9.14 +/- 0.24 ms (n = 35). No correlation was found between the amplitude of the EPSC and the rise time or decay time-constant. The non-N-methyl-D-aspartate (NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione completely blocked the EPSC whereas the NMDA antagonist D-aminophosphonovaleric acid (APV) had modest effects. 3. When a test (T-)EPSC was preceded at an interval of 100 ms by a conditioning (C-)EPSC, a significant increase in the amplitude of the T-EPSC was seen in 38 out of 44 trials analyzed from a total of 27 granule cells. The average amount of PPF was 35.7 +/- 2.1%. There was no apparent correlation between the amount of PPF and the stimulation intensity or mean amplitude of the C-EPSC. The time course of the facilitated T-EPSC was not significantly different from that of the C-EPSC. 4. No correlation was found between the amplitude of the C-EPSC and that of the T-EPSC. Estimates of quantal content (mcv) were determined by calculating the ratio of the squared averaged EPSC amplitude (from 48 responses) to the variance of these responses (M2/sigma 2) whereas quantal amplitudes (qcv) were estimated by calculating the ratio of the response variance to average EPSC amplitude (sigma 2/M). PPF was found to be associated with an average increase in mcv of 64.8 +/- 7.2% (n = 38) whereas qcv was decreased by 12.1 +/- 3.8%. 5. The time course of PPF was studied by varying the interval between the C- and T-pulse from 10 to 400 ms while keeping the stimulation intensity constant. Maximal facilitation of the T-EPSC was obtained with interpulse intervals < or = 25 ms where the average facilitation amounted to approximately 70% (n = 6). The decline of facilitation was nearly exponential and was no longer evident with intervals > 350 ms.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Altered desensitization produces enhancement of EPSPs in neocortical neurons.

1. Neocortical brain slices were prepared from rats (35-50 days of age) and maintained in vitro. Intracellular recordings were obtained from neurons in cortical layers II/III. The effect of bath application of cyclothiazide (CYZ), a potent blocker of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor desensitization, on evoked synaptic activity and passive membrane properties was investigated. 2. Bath application of CYZ did not significantly affect resting membrane potential, input resistance, or repetitive firing. CYZ increased both the amplitude and duration of evoked excitatory postsynaptic potentials (EPSPs). Polysynaptic responses were also augumented. These effects persisted after the blockade of N-methyl-D-aspartate (NMDA) receptors with D-2-amino-5-phosphonovaleric acid (D-APV). The magnitude of these effects appeared to vary directly with stimulation intensity and presumably, amount of glutamate release. 3. Epileptiform activity was induced by bath application of bicuculline methiodide. The amplitude and duration of evoked paroxysmal discharges were increased by CYZ. Similar results were seen in presence of D-APV. 4. These results indicate that CYZ has significant effects on synaptic transmission. Desensitization of non-NMDA receptors may be an important mechanism for determining the time course of EPSPs and in curtailing epileptiform responses in the rat neocortex.

2-Amino-5-phosphonovalerate↗