Changes in inhibitory neurotransmission in the CA1 region and dentate gyrus in a chronic model of temporal lobe epilepsy

1995 ◽  
Vol 74 (2) ◽  
pp. 829-840 ◽  
Author(s):  
P. S. Mangan ◽  
D. A. Rempe ◽  
E. W. Lothman
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Dentate Gyrus ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Ca1 Pyramidal Cells ◽  
Ca1 Region ◽  
Stratum Lacunosum Moleculare ◽  
Reversal Potentials

1. In this report we compare changes in inhibitory neurotransmission within the CA1 region and the dentate gyrus (DG) in a model of chronic temporal lobe epilepsy (TLE). Extracellular and intracellular recordings were obtained in combined hippocampal-parahippocampal slices > or = 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. 2. Polysynaptic inhibitory postsynaptic potentials (IPSPs) were induced by positioning electrodes to activate specific afferent pathways and evoking responses in the absence of glutamate receptor antagonists [D(-)-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)]. Polysynaptic IPSPs were evoked in CA1 pyramidal cells from electrodes positioned in stratum radiatum and in stratum lacunosum/moleculare. Polysynaptic IPSPs were evoked in DG granule cells from electrodes positioned over the perforant path located in the subiculum. Monosynaptic IPSPs were induced by positioning electrodes within 200 microns of the intracellular recording electrode (near site stimulation) and stimulating in the presence of APV and CNQX to block ionotropic glutamate receptors. Monosynaptic IPSPs were evoked in CA1 pyramidal cells with electrodes positioned in the stratum lacunosum/moleculare and stratum pyramidale. Monosynaptic IPSPs were evoked in DG granule cells with electrodes positioned in the stratum moleculare. 3. Population spike (PS) amplitudes were employed to assure that a full range of stimulus strengths, from subthreshold for action potentials to an intensity giving maximal-amplitude PSs, was used to elicit polysynaptic IPSPs in CA1 pyramidal cells in both post-SSLSE and control slices. In control tissue, polysynaptic IPSPs were biphasic, composed of early and late events. In post-SSLSE tissue, polysynaptic IPSPs were markedly diminished. The diminution of polysynaptic IPSPs was detected at all levels of stimulus intensity. Both early IPSPs [mediated by gamma-aminobutyric acid-A (GABAA) receptors] and late IPSPs (mediated by GABAB receptors) were diminished. Polysynaptic IPSPs were diminished with both stratum radiatum and with stratum lacunosum/moleculare stimulation. 4. Reversal potentials for either polysynaptic early or polysynaptic late IPSPs evoked in CA1 pyramidal cells by stratum radiatum stimulation were not different in slices from post-SSLSE animals as compared with control animals. Likewise, reversal potentials for either polysynaptic early or polysynaptic late IPSPs evoked by stratum lacunosum/moleculare stimulation did not differ in the two groups. These findings excluded changes in driving force as an explanation for the diminished amplitude of IPSPs in CA1 pyramidal cells in the post-SSLSE model.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in excitatory neurotransmission in the CA1 region and dentate gyrus in a chronic model of temporal lobe epilepsy

1995 ◽  
Vol 74 (2) ◽  
pp. 841-848 ◽  
Author(s):  
E. W. Lothman ◽  
D. A. Rempe ◽  
P. S. Mangan
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Dentate Gyrus ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Pyramidal Cells ◽  
Postsynaptic Potentials ◽  
Ca1 Pyramidal Cells ◽  
Control Tissue ◽  
Ca1 Region ◽  
Excitatory Neurotransmission

1. In this report we compare changes of excitatory neurotransmission within the CA1 region and the dentate gyrus (DG) in a model of chronic temporal lobe epilepsy (TLE). Extracellular and intracellular recordings were obtained from in vitro hippocampal-parahippocampal slices > or = 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. Pyramidal cells in CA1 were activated by electrodes in the stratum lacunosum/moleculare or stratum radiatum. Granule cells in DG were similarly activated by electrodes positioned in the perforant path. 2. Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked in CA1 pyramidal cells in post-SSLSE tissue were always longer than those evoked in control tissue, irrespective of whether hyperresponsiveness was present or not. EPSPs elicited by stimulus subthreshold for action potentials (APs) in post-SSLSE and in control slices and matched in amplitude had a statistically greater duration in the post-SSLSE slices. Durations of monosynaptic EPSPs elicited by stimuli subthreshold for APs in DG granule cells in post-SSLSE slices were not longer than EPSPs of equal amplitude elicited in control slices. 3. Higher-intensity stimuli produced EPSPs with associated APs and, in certain cases in the post-SSLSE tissue, hyperresponsive events with multiple (> or = 3) APs. Durations of depolarizing profiles with stimuli producing APs were overall longer in both CA1 pyramidal cells and DG granule cells and correlated with the degree of hyperresponsiveness. 4. Neither the amplitudes nor the durations of monosynaptic EPSPs evoked in CA1 pyramidal cells in slices from control animals were affected by the addition of D(-)-2-amino-5-phosphonovaleric acid (APV), a blocker of the N-methyl-D-aspartate (NMDA) receptor, to the artificial cerebrospinal fluid (ACSF) bathing the slices. In contrast to the situation in control tissue, in post-SSLSE tissue APV shortened EPSPs evoked in CA1 pyramidal cells while not changing their amplitudes. After APV, inhibitory postsynaptic potentials (IPSPs) remained greatly diminished or absent in CA1 pyramidal cells. APV did not statistically decrease amplitudes of monosynaptic EPSPs evoked in DG granule cells in either control slices or post-SSLSE slices. APV decreased EPSP durations in both types of slices, more so in the post-SSLSE tissue. 5. In control slices, APV did not change the amplitudes or durations of depolarizing profiles of responses evoked by stimuli producing APs in CA1. Similarly, APV did not change the amplitudes of such responses in DG. However, APV did reduce the durations of such responses in DG in control slices.(ABSTRACT TRUNCATED AT 400 WORDS)

Interneurons in Area CA1 Stratum Radiatum and Stratum Oriens Remain Functionally Connected to Excitatory Synaptic Input in Chronically Epileptic Animals

1997 ◽  
Vol 78 (3) ◽  
pp. 1504-1515 ◽  
Author(s):  
D. A. Rempe ◽  
E. H. Bertram ◽  
J. M. Williamson ◽  
E. W. Lothman
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Synaptic Input ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Ca1 Pyramidal Cells ◽  
Control Tissue ◽  
Stratum Oriens ◽  
Area Ca1 ◽  
Excitatory Synaptic Input

Rempe, D. A., E. H. Bertram, J. M. Williamson, and E. W. Lothman. Interneurons in area CA1 stratum radiatum and stratum oriens remain functionally connected to excitatory synaptic input in chronically epileptic animals. J. Neurophysiol. 78: 1504–1515, 1997. Past work has demonstrated a reduction of stimulus-evoked inhibitory input to hippocampal CA1 pyramidal cells in chronic models of temporal lobe epilepsy (TLE). It has been postulated that this reduction in inhibition results from impaired excitation of inhibitory interneurons. In this report, we evaluate the connectivity of area CA1 interneurons to their excitatory afferents in hippocampal-parahippocampal slices obtained from a rat model of chronic TLE. Rats were made chronically epileptic by a period of continuous electrical stimulation of the hippocampus, which establishes an acute condition of self-sustained limbic status epilepticus (SSLSE). This period of SSLSE is followed by a development of chronic recurrent spontaneous limbic seizures that are associated with chronic neuropathological changes reminiscent of those encountered in human TLE. Under visual control, whole cell patch-clamp recordings of interneurons and pyramidal cells were obtained in area CA1 of slices taken from adult, chronically epileptic post-SSLSE rats. Neurons were activated by means of electrodes positioned in stratum radiatum. Intrinsic membrane properties, including resting membrane potential, action potential (AP) threshold, AP half-height width, and membrane impedance, were unchanged in interneurons from chronically epileptic (post-SSLSE) tissue compared with control tissue. Single stimuli delivered to stratum radiatum evoked depolarizing excitatory postsynaptic potentials and APs in interneurons, whereas paired-pulse stimulation evoked facilitation of the postsynaptic current (PSC) in both control and post-SSLSE tissue. No differences between interneurons in control versus post-SSLSE tissue could be found with respect to the mean stimulus intensity or mean stimulus duration needed to evoke an AP. A multiple linear regression analysis over a range of stimulus intensities demonstrated that a greater number of APs could be evoked in interneurons in post-SSLSE tissue compared with control tissue. Spontaneous PSCs were observed in area CA1 interneurons in both control and post-SSLSE tissue and were markedly attenuated by glutamatergic antagonists. In conclusion, our data suggest that stimulus-evoked and spontaneous excitatory synaptic input to area CA1 interneurons remains functional in an animal model of chronic temporal lobe epilepsy. These findings suggest, therefore, that the apparent decrease of polysynaptic inhibitory PSPs in CA1 pyramidal cells in epileptic tissue is not due to a deficit in excitatory transmission from Schaffer collaterals to interneurons in stratum radiatum and straum oriens.

Regional heterogeneity of pathophysiological alterations in CA1 and dentate gyrus in a chronic model of temporal lobe epilepsy

1995 ◽  
Vol 74 (2) ◽  
pp. 816-828 ◽  
Author(s):  
D. A. Rempe ◽  
P. S. Mangan ◽  
E. W. Lothman
Keyword(s):  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Dentate Gyrus ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Pyramidal Cells ◽  
Stimulus Strength ◽  
Input Output ◽  
Maximal Amplitude ◽  
Control Tissue

1. Extracellular and intracellular recording techniques were employed in brain slice preparations to characterize responses of hippocampal tissue in the post-self sustaining limbic status epilepticus (post-SSLSE) model of chronic temporal lobe epilepsy (TLE) as compared with responses in slices from control animals. Experiments were performed > or = 1 mo, and up to 7 mo, after status epilepticus. Two regions of the hippocampal formation linked to different aspects of epileptogenesis, the CA1 region and the dentate gyrus (DG), were studied. In any given experiment, CA1 and DG were examined in different slices from the same animal. 2. Pyramidal cells in CA1 were activated by means of electrodes positioned over fiber bundles that monosynaptically project to these cells, either those located in the stratum lacunosum/moleculare or those in the stratum radiatum. Granule cells were similarly activated by electrodes positioned in the perforant path. Full input-output curves were determined by varying stimulus strength and charting the amplitudes of population spikes (PSs). 3. Two indexes, stimulus sensitivity and responsiveness, were quantified in control tissue and in post-SSLSE tissue by means of input-output curves to provide comparisons between normal and epileptic tissue. There were no changes in stimulus sensitivity, defined as the stimulus intensity required to evoke comparable responses in input-output curves, between control and post-SSLSE tissue. However, responsiveness, defined as the number of extracellular PSs or intracellular action potentials (APs) elicited by a stimulus strength giving rise to maximal-amplitude PSs, proved a reliable method for identifying and categorizing epileptic responses. This index allowed for comparisons between anatomic regions within an experiment as well as among experiments for the same region. Both CA1 pyramidal cells and DG granule cells from post-SSLSE tissue showed hyperresponsiveness relative to control tissue. 4. Control tissue never exhibited > 2 PSs in either CA1 or DG in response to stimuli that produced maximal-amplitude PSs. Therefore a criterion of > or = 3 PSs was adopted to delineate tissue as hyperresponsive on the basis of extracellular responses. In CA1 about one half of the post-SSLSE slices displayed > or = 3 PSs with stimuli giving maximal-amplitude PSs, meeting the criterion for hyperresponsiveness; in DG about one fifth of the slices showed hyperresponsiveness. 5. CA1 and DG differed with respect to the spectrum of hyperresponsiveness they exhibited, this being more robust in CA1. The two regions studied also showed heterogeneity with respect to maximal PS amplitudes.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy

2012 ◽  
Vol 420 (1) ◽  
pp. 156-160 ◽  
Author(s):  
Rainer Surges ◽  
Maria Kukley ◽  
Amy Brewster ◽  
Christiane Rüschenschmidt ◽  
Johannes Schramm ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Dentate Gyrus ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Cation Current

Cell-Specific Alterations in Synaptic Properties of Hippocampal CA1 Interneurons After Kainate Treatment

1998 ◽  
Vol 80 (6) ◽  
pp. 2836-2847 ◽  
Author(s):  
F. Morin ◽  
C. Beaulieu ◽  
J.-C. Lacaille
Keyword(s):  
Time Constant ◽  
Decay Time ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Inhibitory Interneurons ◽  
Cell Type ◽  
Postsynaptic Currents ◽  
Ca1 Region ◽  
Hippocampal Ca1 ◽  
Stratum Lacunosum Moleculare

Morin, F., C. Beaulieu, and J.-C. Lacaille. Cell-specific alterations in synaptic properties of hippocampal CA1 interneurons after kainate treatment. J. Neurophysiol. 80: 2836–2847, 1998. Hippocampal sclerosis and hyperexcitability are neuropathological features of human temporal lobe epilepsy that are reproduced in the kainic acid (KA) model of epilepsy in rats. To assess directly the role of inhibitory interneurons in the KA model, the membrane and synaptic properties of interneurons located in 1) stratum oriens near the alveus (O/A) and 2) at the border of stratum radiatum and stratum lacunosum-moleculare (LM), as well as those of pyramidal cells, were examined with whole cell recordings in slices of control and KA-lesioned rats. In current-clamp recordings, intrinsic cell properties such as action potential amplitude and duration, amplitude of fast and medium duration afterhyperpolarizations, membrane time constant, and input resistance were generally unchanged in all cell types after KA treatment. In voltage-clamp recordings, the amplitude and conductance of pharmacologically isolated excitatory postsynaptic currents (EPSCs) were significantly reduced in LM interneurons of KA-treated animals but were not significantly changed in O/A and pyramidal cells. The rise time of EPSCs was not significantly changed in any cell type after KA treatment. In contrast, the decay time constant of EPSCs was significantly faster in O/A interneurons of KA-treated rats but was unchanged in LM and pyramidal cells. The amplitude and conductance of pharmacologically isolated γ-aminobutyric acid-A (GABAA) inhibitory postsynaptic currents (IPSCs) were not significantly changed in any cell type of KA-treated rats. The rise time and decay time constant of GABAA IPSCs were significantly faster in pyramidal cells of KA-treated rats but were not significantly changed in O/A and LM interneurons. These results suggest that complex alterations in synaptic currents occur in specific subpopulations of inhibitory interneurons in the CA1 region after KA lesions. A reduction of evoked excitatory drive onto inhibitory cells located at the border of stratum radiatum and stratum lacunosum-moleculare may contribute to disinhibition and polysynaptic epileptiform activity in the CA1 region. Compensatory changes, involving excitatory synaptic transmission on other interneuron subtypes and inhibitory synaptic transmission on pyramidal cells, may also take place and contribute to the residual, functional monosynaptic inhibition observed in principal cells after KA treatment.

scholarly journals Adaptive Intrinsic Plasticity in Human Dentate Gyrus Granule Cells during Temporal Lobe Epilepsy

2011 ◽  
Vol 22 (9) ◽  
pp. 2087-2101 ◽  
Author(s):  
M. Stegen ◽  
F. Kirchheim ◽  
A. Hanuschkin ◽  
O. Staszewski ◽  
R. W. Veh ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Dentate Gyrus ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Intrinsic Plasticity

Hippocampal Interneurons Are Excited Via Serotonin-Gated Ion Channels

1997 ◽  
Vol 78 (5) ◽  
pp. 2493-2502 ◽  
Author(s):  
Lori L. McMahon ◽  
Julie A. Kauer
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Negative Slope ◽  
Patch Clamp Recording ◽  
Gated Ion Channels

McMahon, Lori L. and Julie A. Kauer. Hippocampal interneurons are excited via serotonin-gated ion channels. J. Neurophysiol. 78: 2493–2502, 1997. Serotonergic neurons of the median raphe nucleus heavily innervate hippocampal GABAergic interneurons located in stratum radiatum of area CA1, suggesting that this strong subcortical projection may modulate interneuron excitability. Using whole cell patch-clamp recording from interneurons in brain slices, we tested the effects of serotonin (5-HT) on the physiological properties of these interneurons. Serotonin produces a rapid inward current that persists when synaptic transmission is blocked by tetrodotoxin and cobalt, and is unaffected by ionotropic glutamate and γ-aminobutyric acid (GABA) receptor antagonists. The 5-HT–induced current was independent of G-protein activation. Pharmacological evidence indicates that 5-HT directly excites these interneurons through activation of 5-HT3 receptors. At membrane potentials negative to −55 mV, the current-voltage ( I-V) relationship of the 5-HT current displays a region of negative slope conductance. Therefore the response of interneurons to 5-HT strongly depends on membrane potential and increases greatly as cells are depolarized. Removal of extracellular calcium, but not magnesium, increases the amplitude of 5-HT–induced currents and removes the region of negative slope conductance, thereby linearizing the I-V relationship. The axons of 5-HT–responsive interneurons ramify widely within CA1; some of these interneurons also project to and arborize extensively in the dentate gyrus. The organization of these inhibitory connections strongly suggests that these cells regulate excitability of both CA1 pyramidal cells and dentate granule cells. As our results indicate that 5-HT may mediate fast excitatory synaptic transmission onto these interneurons, serotonergic inputs can simultaneously modulate the output of both hippocampus and dentate gyrus.

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.

Entorhinal inputs to hippocampal CA1 and dentate gyrus in the rat: a current-source-density study

1995 ◽  
Vol 73 (6) ◽  
pp. 2392-2403 ◽  
Author(s):  
L. S. Leung ◽  
L. Roth ◽  
K. J. Canning
Keyword(s):  
Dentate Gyrus ◽  
Cell Body ◽  
Granule Cells ◽  
Current Source ◽  
Pyramidal Cells ◽  
Short Latency ◽  
Current Source Density ◽  
Perforant Path ◽  
Stratum Radiatum ◽  
Source Density

1. Laminar profiles of the average evoked potentials and current-source-density analysis were used to study the input provided by the medial perforant path (PP) to the hippocampus in the urethan-anesthetized rat. 2. Stimulation of the PP activated an early latency sink in the middle molecular layer of the dentate gyrus (DG) and in the stratum lacunosum-moleculare in CA1. The DG current sink was generated by excitatory synaptic currents activated by the PP on dentate granule cells. In the normal rat, the peak current sink in the DG was typically five times greater than that of CA1. However, the CA1 sink could be distinguished from the DG sink in several ways: 1) it peaked when the DG sink was subsiding; 2) it showed paired-pulse facilitation, whereas the DG sink did not; and 3) in rats in which the DG was lesioned by local colchicine injection, the DG sink was reduced much more than the CA1 sink. 3. The PP afferents to CA1 required a slightly higher stimulus threshold (> 100 microA) for activation than those projecting to the DG granule cells (< 30 microA). The onset latency of the early CA1 sink (2.5 +/- 0.2 ms, mean +/- SE) was also slightly longer than that of the DG sink (1.7 +/- 0.1 ms), suggesting that the axons of entorhinal layer III cells that project to CA1 have a slightly lower conduction velocity than the axons of the layer II cells that project to the DG. 4. The short-latency current sink activated by the PP in the distal dendritic layers of CA1 was likely provided by excitatory currents at the distal apical dendrites of CA1 pyramidal cells. The accompanying current source was mainly confined to stratum radiatum and appeared not to involve the cell body layer. Thus the electrotonic current spread may not be effective enough to depolarize the cell body or axon hillock. Contribution of interneurons to the above source-sink profile is possible, with the provision that these interneurons must have dendritic processes that span strata radiatum and lacunosum moleculare. 5. Extracellular field recordings provided no evidence that PP evoked a short-latency (< 9 ms) CA1-generated population spike, even with the use of micropipettes filled with mM bicuculline. Similarly, unit recordings in CA1 revealed only long-latency (9-17 ms) unit firing after PP stimulation, corresponding to a late, di/trisynaptic excitation of CA1 via the Schaffer collaterals.(ABSTRACT TRUNCATED AT 400 WORDS)

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