Cessation of spermatogenesis in juvenile spermatogonial depletion (jsd/jsd) mice

Several lines of evidence have suggested that decreases in postsynaptic inhibition may have a role in epileptogenesis in cortical structures. However, other studies have suggested that GABAergic inhibition is spared, or even augmented in some forms of post-lesional epilepsy. In the studies described here, inhibitory events were recorded in two models of post-lesional chronic epileptogenesis. (i) As previously reported (D.A. Prince and G.-F. Tseng. J. Neurophysiol. 69: 1276-1291. 1993), epileptiform activity develops in slices from partially isolated rat neocortical islands 2-3 weeks after the initial in vivo lesion. In this model of post-traumatic epilepsy, large amplitude polyphasic inhibitory postsynaptic currents (IPSCs) in layer V pyramidal neurons are associated with each interictal epileptiform field potential. The frequency of spontaneous IPSCs as well as miniature IPSCs was significantly increased in neocortical slices from the epileptogenic chronically injured cortex versus controls. Immunocytochemical reactions for parvalbumin and calbindin, calcium binding proteins present in subgroups of GABAergic neurons, showed an increased staining of both neuropil and somata within the epileptogenic tissue. Immunoreactivity for glutamic acid decarboxylase (GAD) and GABA also appeared to be increased in the neuropil. (ii) Cortical microgyri resembling human malformations were produced by freeze lesions made transcranially in P0 rat cortex (K.M. Jacobs, M.J. Gutnick, and D.A. Prince. Cereb. Cortex, 6: 514-523. 1996). The boundary between the four-layered microgyrus and surrounding cortex become epileptogenic within about 2 weeks, as judged by evoked extracellular field potentials and cellular activities. Epileptogenesis in the surrounding cortex is not altered when the microgyrus itself is isolated by transcortical cuts. Patch-clamp recordings from layer V neurons in the epileptogenic zone showed that spontaneous IPSCs are larger and more dependent on glutamatergic synapses than in control neurons. The amplitudes of polysynaptic IPSCs evoked by threshold stimulation were also larger than in control cells. Although evaluation of inhibitory events in these models is still incomplete, results to date suggest that GABAergic inhibition may be enhanced in epileptogenic areas associated with chronic cortical injury. Sprouting of axonal arborizations of pyramidal cells onto interneurons, upregulation of GABAergic neurons, and perhaps sprouting of inhibitory axons that make increased numbers of contacts onto pyramidal cells may all contribute to the increased inhibitory drive. Results in these models do not support the disinhibitory hypothesis of chronic epileptogenesis.     

Cell-specific alterations in synaptic properties of hippocampal CA1 interneurons after kainate treatment

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 gamma-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.     

High-performance liquid-phase separation of glycosides. III. Determination of total glucosinolates in cabbage and rapeseed by capillary electrophoresis via the enzymatically released glucose

Alterations in synaptic inhibition are associated with epileptiform activity in several acute animal models; however, it is not clear if there are changes in inhibition in chronically epileptic tissue. We have used intracellular recordings from granule cells of patients with temporal lobe epilepsy to determine whether synaptic inhibition is compromised. Two groups of patients with medial temporal lobe epilepsy were used, those with medial temporal lobe sclerosis (MTLE), and those with extrahippocampal masses (MaTLE) where the cell loss and synaptic reorganization that characterize MTLE are not seen. Although the level of tonic inhibition at the somata was not significantly different in the two patient groups, there was a reduction in the conductance of polysynaptic perforant path-evoked fast and slow inhibitory postsynaptic potentials (IPSPs) (53% and 66%, respectively). We found that there was a comparable decrease in the monosynaptic IPSP conductances examined in the presence of glutamatergic antagonists as that seen for the polysynaptically evoked IPSPs. These data suggest that the decrease in inhibition seen in normal artificial cerebrospinal fluid in MTLE granule cells cannot be solely explained by a decrease in excitatory input onto inhibitory interneurons and may reflect changes at the interneuron-granule cells synapse or in the number of specific inhibitory interneurons.     

Synaptic effects of identified interneurons innervating both interneurons and pyramidal cells in the rat hippocampus

GABAergic interneurons sculpt the activity of principal cells and are themselves governed by GABAergic inputs. To determine directly some of the sources and mechanisms of this GABAergic innervation, we have used dual intracellular recordings with biocytin-filled microelectrodes and investigated synaptic interactions between pairs of interneurons in area CA1 of the adult rat hippocampus. Of four synaptically-coupled interneuron-to-interneuron cell pairs, three presynaptic cells were identified as basket cells, preferentially innervating somata and proximal dendrites of pyramidal cells, but one differing from the other two in the laminar distribution of its dendritic and axonal fields. The fourth presynaptic interneuron was located at the border between strata lacunosum moleculare and radiatum, with axon ramifying within stratum radiatum. Action potentials evoked in all four presynaptic interneurons were found to elicit fast hyperpolarizing inhibitory postsynaptic potentials (mean amplitude 0.35 +/- 0.10 mV at a membrane potential of -59 +/- 2.8 mV) in other simultaneously recorded interneurons (n=4). In addition, three of the presynaptic interneurons were also shown to produce similar postsynaptic responses in subsequently recorded pyramidal cells (n=4). Electron microscopic evaluation revealed one of the presynaptic basket cells to form 12 synaptic junctions with the perisomatic domain (seven somatic synapses and five synapses onto proximal dendritic shafts) of the postsynaptic interneuron in addition to innervating the same compartments of randomly-selected local pyramidal cells (50% somatic and 50% proximal dendritic synapses, n=12). In addition, light microscopic analysis also indicated autaptic self-innervation in basket (12 of 12) and bistratified cells (six of six). Electron microscopic investigation of one basket cell confirmed six autaptic junctions made by five of its boutons. Together, these data demonstrate that several distinct types of interneuron have divergent output to both principal cells and local interneurons of the same (basket cells) or different type. The fast synaptic effects, probably mediated by GABA in both postsynaptic interneurons and principal cells are similar. These additional sources of GABA identified here in the input to GABAergic cells could contribute to the differential temporal patterning of distinct GABAergic synaptic networks.     

GABA--the basic mediator of excitation in the early stages of hippocampal development

GABA is the principal neurotransmitter of inhibition in the adult mammalian brain. However, at early stages of development, including embryonic period and first week of postnatal life, GABA plays the role of main neurotransmitter of excitation. The paradoxical excitatory effect of GABA is due to an inversed chloride gradient and therefore a depolarizing direction of GABA-A receptor mediated responses. In addition, another type of GABAergic inhibition mediated by postsynaptic GABA-B receptors is not functional at early stage of life. In the neonatal rat hippocampus, GABA, acting via GABA-A receptors, activates voltage gated sodium and calcium channels and potentiates the activity of NMDA receptors by reducing their voltage dependent Mg2+ block. The temporal window when GABA exerts excitatory actions coincides with a particular pattern of activity of hippocampal neuronal network that is characterized by periodical giant depolarizing potentials (GDPs) reminiscent of interictal-like epileptiform discharges. Recent studies have shown that GDPs result from the synchronous discharge of GABAergic interneurons and principal glutamatergic pyramidal cells and are mediated by the synergistic excitatory actions of GABA-A and glutamate receptors. GDPs provide synchronous intracellular Ca2+ oscillations and may therefore be implicated in hebbian modulation of developing synapses and activity-dependent formation of the hippocampal network.     

Malignant lesions presenting as symptoms of craniomandibular dysfunction

We compared the findings of scalp electroencephalogram with subdural electrode array (SEA) recordings in 19 patients with refractory frontal lobe epilepsy. Prolonged scalp interictal recordings localized the epileptogenic zone in 12 patients; seven had no interictal sharp waves. The SEAs showed multifocal interictal sharp waves in all patients. Seven patients with localized seizure onset on scalp recording showed extensive ictal onset on the SEA recording. Five patients with lateralized seizure onset to one hemisphere on scalp recording were found to have ictal onset on SEA restricted to a smaller area. Because of the large epileptogenic zone found on SEA recordings, a complete resection was possible in only five (33%) of the 15 patients who had resections. Eight (53%) of the 15 patients benefited from surgery (mean follow-up, 4.6 years). The SEAs also allowed functional localization in most patients. From these data, we suggest that a localizing scalp electroencephalogram in patients with frontal lobe epilepsy may be misleading because SEA recordings show larger epileptogenic zones than anticipated. Furthermore, we postulate that the larger extensive epileptogenic zone may account for the poorer surgical outcome in patients with frontal lobe epilepsy compared with patients with temporal lobe epilepsy.     

A stereoelectroencephalographic (SEEG) study of light-induced mesiotemporal epileptic seizures

PURPOSE: This study explored the mechanism of light-induced complex partial seizures by using ictal intracerebral recordings in a patient with refractory epilepsy of the right temporal lobe. METHODS: Presurgical evaluation of this patient was realized by means of video-EEG recordings, WADA test, magnetic resonance imaging (MRI), F18-deoxyglucose and C11-flumazenil positron emission tomography (PET) interictal neuroimaging data, and stereoelectroencephalographic (SEEG) ictal recordings. RESULTS: SEEG investigations demonstrated the right mesiotemporal origin of all the patient's seizures. This result was confirmed by a successful right temporal lobectomy. Moreover, SEEG recordings revealed a frequent interictal spiking activity in the right occipital visual cortex that was undetectable on scalp recordings. However, the occipital cortex was not involved at the onset of mesiotemporal ictal discharges and was not hyperresponsive to focal electrical stimulation. CONCLUSIONS: This study shows that, in spite of interictal occipital spiking, the photosensitivity of mesiotemporal seizures can be observed in both the absence of occipital cortex involvement during ictal discharges and demonstrable hyperexcitability of the occipital cortex to light or direct electrical stimulation.     

5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus

5-Hydroxytryptamine (5-HT; serotonin) administration enhances GABAergic synaptic activity recorded in pyramidal neurons of the CA1 region of hippocampus. Previous studies have attributed this effect to the activation of HT-5(3) receptors located on GABAergic interneurons. During unrelated experiments, we noticed that under our recording conditions, 5-HT can still increase GABAergic synaptic activity after the complete blockade of 5-HT3 receptors. This indicated the involvement of an additional 5-HT receptor subtype. Therefore, we reinvestigated the effects of 5-HT on GABAergic synaptic activity recorded in pyramidal cells of the CA1 region. The ability of 5-HT to increase GABAergic synaptic activity in the presence of 5-HT3 receptor blockade was mimicked by the selective 5-HT2 agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and blocked by the selective 5-HT2 antagonist ketanserin. This indicated that the additional 5-HT receptor belongs to 5-HT2 receptor family. 5-HT2 receptor activation resulted in an increase in the frequency of spontaneous inhibitory postsynaptic currents as well as a shift in their amplitude distribution toward larger sizes. These effects were absent in the presence of tetrodotoxin. We interpret these results to indicate that 5-HT2 receptors activate GABAergic interneurons in the slice, leading to an increase in GABAergic synaptic activity onto pyramidal cells of the CA1 region.     

Hypothetical mechanisms for the cellular and neurophysiologic basis of secondary epileptogenesis: proposed role of synaptic reorganization

This review article evaluates the hypothetical cellular mechanisms responsible for chronic lesion-induced epilepsy. Emphasis is given to particular clinical characteristics of secondary epileptogenesis: (a) a temporal latency, (b) the involvement of distant but related sites, and (c) irreversibility. Although loss of GABAergic inhibitory interneurons or increased excitatory input to these interneurons may contribute to epileptogenesis, several studies have provided evidence that inhibition is not depressed in epileptogenic regions and may actually be enhanced. Axonal sprouting, synaptic reorganization, and formation of new recurrent excitatory circuits have been proposed to account for the increased seizure susceptibility of temporal lobe epilepsy. Recent data support the hypothesis that local inhibitory circuits mask the multisynaptic excitatory interactions that are associated with mossy fiber sprouting in the dentate gyrus and that physiological mechanisms that reduce inhibition or increase excitability unmask the new recurrent excitatory circuits responsible for seizures. A hypothesis based on axonal sprouting and synaptic reorganization can account for the essential clinical characteristics of secondary epileptogenesis and may have widespread applicability to the general phenomenon of lesion-induced epilepsy.     

EEG findings in frontal lobe epilepsies

As a group, epilepsies of frontal lobe origin are thought to be poorly localized using surface EEG recordings. This finding may depend on the specific areas of frontal lobe from which the seizures originate or the pathologic substrate. We reviewed the presurgical surface EEGs of patients with frontal lobe epilepsy who underwent epilepsy surgery. The specific area of the frontal lobe where seizures originated was determined by 1) intracranial ictal EEG recordings, or 2) the presence of a structural lesion, identified by imaging studies in patients who achieved complete seizure control following surgery. We differentiated patients whose seizures began in the dorsolateral frontal convexity from those whose seizures began in the medial frontal region, and we correlated EEG findings in the interictal, postictal, and ictal states with seizure semiology, pathologic substrate, and surgical outcome. Four of nine patients had seizures originating in the dorsolateral frontal convexity and five had medial frontal onset seizures. Patients whose seizures originated from the dorsolateral convexity had focal interictal epileptiform abnormalities that localized to the region of seizure onset. Patients whose seizures began in the medial frontal region had either no interictal epileptiform abnormality or had multifocal epileptiform discharges. Patients whose seizures began in the dorsolateral convexity showed focal electrographic seizure activity that was localizing. This rhythmic fast activity did not appear to be substrate-specific. Patients whose seizure onset localized to the medial frontal region did not show focal electrographic seizure at clinical onset. We conclude that the scalp EEG recordings of frontal lobe epilepsies contain features that enable differentiation of seizures originating from two different regions of the frontal lobe.     

Intracellular and computational characterization of the intracortical inhibitory control of synchronized thalamic inputs in vivo

We investigated the presence and role of local inhibitory cortical control over synchronized thalamic inputs during spindle oscillations (7-14 Hz) by combining intracellular recordings of pyramidal cells in barbiturate-anesthetized cats and computational models. The recordings showed that 1) similar excitatory postsynaptic potential (EPSP)/inhibitory postsynaptic potential (IPSP) sequences occurred either during spindles or following thalamic stimulation; 2) reversed IPSPs with chloride-filled pipettes transformed spindle-related EPSP/IPSP sequences into robust bursts with spike inactivation, resembling paroxysmal depolarizing shifts during seizures; and 3) dual simultaneous impalements showed that inhibition associated with synchronized thalamic inputs is local. Computational models were based on reconstructed pyramidal cells constrained by recordings from the same cells. These models showed that the transformation of EPSP/IPSP sequences into fully developed spike bursts critically needs a relatively high density of inhibitory currents in the soma and proximal dendrites. In addition, models predict significant Ca2+ transients in dendrites due to synchronized thalamic inputs. We conclude that synchronized thalamic inputs are subject to strong inhibitory control within the cortex and propose that 1) local impairment of inhibition contributes to the transformation of spindles into spike-wave-type discharges, and 2) spindle-related inputs trigger Ca2+ events in cortical dendrites that may subserve plasticity phenomena during sleep.     

Acetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells

The effects of acetylcholine on both pyramidal neurons and interneurons in the area CA1 of the rat hippocampus were examined, using intracellular recording techniques in an in vitro slice preparation. In current-clamp mode, fast local application of acetylcholine (ACh) to the soma of inhibitory interneurons in stratum radiatum resulted in depolarization and rapid firing of action potentials. Under voltage-clamp, ACh produced fast, rapidly desensitizing inward currents that were insensitive to atropine but that were blocked by nanomolar concentrations of the nicotinic alpha7 receptor-selective antagonists alpha-bungarotoxin (alphaBgTx) and methyllycaconitine. Nicotinic receptor antagonists that are not selective for alpha7-containing receptors had little (mecamylamine) or no effect (dihydro-beta-erythroidine) on the ACh-induced currents. Glutamate receptor antagonists had no effect on the ACh-evoked response, indicating that the current was not mediated by presynaptic facilitation of glutamate release. However, the current could be desensitized almost completely by bath superfusion with 100 nM nicotine. In contrast to those actions on interneurons, application of ACh to the soma of CA1 pyramidal cells did not produce a detectable current. Radioligand-binding experiments with [125I]-alphaBgTx demonstrated that stratum radiatum interneurons express alpha7-containing nAChRs, and in situ hybridization revealed significant amounts of alpha7 mRNA. CA1 pyramidal cells did not show specific binding of [125I]-alphaBgTx and only low levels of alpha7 mRNA. These results suggest that, in addition to their proposed presynaptic role in modulating transmitter release, alpha7-containing nAChRs also may play a postsynaptic role in the excitation of hippocampal interneurons. By desensitizing these receptors, nicotine may disrupt this action and indirectly excite pyramidal neurons by reducing GABAergic inhibition.     

A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men

Interictal brain SPECT is useful for the localization of a seizure focus. Concomitant hypoperfusion of the ipsilateral thalamus on interictal SPECT has been noted for temporal lobe epilepsy. In this study, we aimed to evaluate the prevalence of thalamic hypoperfusion ipsilateral to temporal hypoperfusion (ipsilateral thalamic hypoperfusion) and to assess the usefulness of this finding for the lateralization of epileptic foci on interictal SPECT for temporal lobe epilepsy patients. METHODS: Forty-six patients with refractory temporal lobe epilepsy underwent interictal brain SPECT after intravenous injection of 555-740 MBq of 99mTc-ECD. Perfusion impairments in the brain, especially the temporal lobe and thalamus, were evaluated. The localization of seizure foci was determined in conjunction with scalp, ictal and cortical electroencephalography, MRI and clinical outcomes. Ictal SPECT was performed for 5 of the 12 patients. RESULTS: Concomitant decreased perfusion in both the temporal lobe and the ipsilateral thalamus was observed for 12 (26%) of 46 temporal lobe epilepsy patients on interictal brain SPECT. Seven patients showed hypoperfusion in the left temporal lobe and ipsilateral thalamus. Five patients showed hypoperfusion in the right temporal lobe and ipsilateral thalamus. In addition, hypoperfusion in the ipsilateral basal ganglia (ten patients) or contralateral cerebellum (four patients) was observed. CONCLUSION: Ipsilateral thalamic hypoperfusion is not uncommon in temporal lobe epilepsy. The exact mechanism causing ipsilateral thalamic hypoperfusion is uncertain; however, corticothalamic diaschisis may be an important factor. This finding may aid in the lateralization of seizure foci on interictal brain SPECT.     

Inhibition evoked from primary afferents in the electrosensory lateral line lobe of the weakly electric fish (Apteronotus leptorhynchus)

Distal versus proximal inhibitory shaping of feedback excitation in the electrosensory lateral line lobe: implications for sensory filtering. J. Neurophysiol. 80: 3214-3232, 1998. The inhibition controlling the indirect descending feedback (parallel fibers originating from cerebellar granule cells in the eminentia posterior pars granularis) to electrosensory lateral line lobe (ELL) pyramidal cells was studied using intracellular recording techniques in vitro. Parallel fibers (PF) contact stellate cells and dendrites of ventral molecular layer (VML) GABAergic interneurons. Stellate cells provide local input to pyramidal cell distal dendrites, whereas VML cells contact their somata and proximal dendrites. Single-pulse stimulation of PF evoked graded excitatory postsynaptic potentials (EPSPs) that were blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl--aspartate (NMDA) antagonists. The EPSPs peaked at 6.4 +/- 1.8 ms (mean +/- SE; n = 11) but took >50 ms to decay completely. Tetanic stimulation (100 ms, 100 Hz) produced a depolarizing wave with individual EPSPs superimposed. The absolute amplitude of the individual EPSPs decreased during the train. Spike rates, established by injected current, mostly were increased, but in some cells were decreased, by tetanic stimulation. Global application of a gamma-aminobutyric acid-A (GABAA) antagonist to the recorded cell's soma and apical dendritic region increased the EPSP peak and decay phase amplitudes. Tetanic stimulation always increased current-evoked spike rates after GABAA blockade during, and for several hundred milliseconds after, the stimulus. Application of a GABAB antagonist did not have any significant effects on the PF-evoked response. This, and the lack of any long hyperpolarizing inhibitory postsynaptic potentials, suggests that VML and stellate cell inhibition does not involve GABAB receptors. Focal GABAA antagonist applications to the dorsal molecular layer (DML) and pyramidal cell layer (PCL) had contrasting effects on PF-evoked EPSPs. DML GABAA blockade significantly increased the EPSP peak amplitude but not the decay phase of the EPSP, whereas PCL GABAA-blockade significantly increased the decay phase, but not the EPSP peak, amplitude. The order of antagonist application did not affect the outcome. On the basis of the known circuitry of the ELL, we conclude that the distal inhibition originated from GABAergic molecular layer stellate cells and the proximal inhibition originated from GABAergic cells of the ventral molecular layer (VML cells). Computer modeling of distal and proximal inhibition suggests that intrinsic differences in IPSP dynamics between the distal and proximal sites may be amplified by voltage-dependent NMDA receptor and persistent sodium currents. We propose that the different time courses of stellate cell and VML cell inhibition allows them to act as low- and high-pass filters respectively on indirect descending feedback to ELL pyramidal cells.     

Facilitation of miniature GABAergic currents by ruthenium red in neonatal rat hippocampal neurons

The whole cell configuration of the patch-clamp technique was used to study the modulation gamma-aminobutyric acid (GABA)-mediated postsynaptic currents by ruthenium red in CA3 hippocampal neurons in slices obtained from postnatal (P) days P6-P10 old rats. In the presence of kynurenic acid (1 mM), ruthenium red (100 microM) completely blocked stimulus-elicited GABA-mediated postsynaptic currents and reduced by 50% the amplitude of the spontaneous ones. Ruthenium red (100 microM) increased the frequency but not the amplitude of miniature GABAergic currents recorded in the presence of tetrodotoxin (1 microM) and kynurenic acid (1 mM), an effect that was prevented by heparin (100 microM). Ruthenium red did not modify the kinetics of miniature postsynaptic currents and the currents induced by exogenous application of GABA (10 microM) in the presence of tetrodotoxin, suggesting that its action was presynaptic in origin. The effects of ruthenium red on quantal GABA release was independent of external calcium. In a nominally Ca2+-free solution the potentiating effect induced by this polyvalent cation on miniature postsynaptic currents was still present. Intracellular calcium stores were not involved in ruthenium red action, because this polyvalent cation was able to facilitate miniature currents also in the presence of thapsigargin (10-20 microM). These results indicate that ruthenium red has a dual action on GABA release from GABAergic interneurons: it reduces the amplitude of spontaneous events and increases the frequency of miniature currents. The former effect is calcium-dependent, whereas the latter is calcium independent.     

Magnetoencephalography in partial epilepsy: clinical yield and localization accuracy

The goals of this study were to determine (1) the yield of magnetoencephalography (MEG) according to epilepsy type, (2) if MEG spike sources colocalize with focal epileptogenic pathology, and (3) if MEG can identify the epileptogenic zone when scalp ictal electroencephalogram (EEG) or magnetic resonance imaging (MRI) fail to localize it. Twenty-two patients with mesial temporal (10 patients), neocortical temporal (3 patients), and extratemporal lobe epilepsy (9 patients) were studied. A 37-channel biomagnetometer was used for simultaneously recording MEG with EEG. During the typical 2-3-hour MEG recording session, interictal epileptiform activity was observed in 16 of 22 patients. MEG localization yield was greater in patients with neocortical epilepsy (92%) than in those with mesial temporal lobe epilepsy (50%). In 5 of 6 patients with focal epileptogenic pathology, MEG spike sources were colocalized with the lesions. In 11 of 12 patients with nonlocalizing (ambiguous abnormalities or normal) MRI, MEG spike sources were localized in the region of the epileptogenic zone as ultimately defined by all clinical and EEG information (including intracranial EEG). In conclusion, MEG can reliably localize sources of spike discharges in patients with temporal and extratemporal lobe epilepsy. MEG sometimes provides noninvasive localization data that are not otherwise available with MRI or conventional scalp ictal EEG.     

Single photon emission computed tomography-EEG relations in temporal lobe epilepsy

The role of single photon emission computed tomography (SPECT) as an independent confirmation test in presurgical evaluation of medically intractable temporal lobe epilepsy has not been critically investigated. Because spreading ictal discharges may cause a concomitant increase of cerebral blood flow in remote cerebral regions, a careful analysis of peri-injection EEG patterns and their relation to ictal SPECT may be important in evaluating the reliability of ictal SPECT. Both interictal and ictal EEG and SPECT were reviewed in 19 patients with temporal lobe epilepsy who achieved a successful seizure outcome after surgery. Patients were divided into unitemporal and bitemporal groups according to the lateralization of interictal epileptiform discharges (IED). Ictal EEG features were classified into lateralized and nonlateralized groups. The concordance between SPECT and EEG lateralizations was examined in each patient and correlated to the documented epileptogenic temporal lobe. Interictal SPECT correctly lateralized in eight of nine patients with unitemporal IED and in five of 10 patients with bitemporal IED. Ictal SPECT was highly concordant with the peri-injection ictal EEG but correctly lateralized the epileptogenic region in only 11 of 19 patients. When both pre- and postinjection EEG epochs lateralized ipsilaterally, all ictal SPECT images showed concordant lateralization. If pre- and postinjection EEG epochs were either different in lateralization or nonlateralization, ictal SPECT images often showed complex patterns of cerebral perfusion with a high incidence of false lateralization. Interictal SPECT was more sensitive and reliable in patients with unitemporal IED than in patients with bitemporal IEDs. Ictal SPECT was closely related with peri-injection EEG epochs but with frequent false lateralization. The role of ictal SPECT as an independent confirmation test in presurgical evaluation should be reappraised.     

Do GABAA and GABAB inhibitory postsynaptic responses originate from distinct interneurons in the hippocampus?

GABAergic inhibition of hippocampal pyramidal cells is mediated by two distinct subtypes of postsynaptic receptors, GABAA and GABAB. Electrical stimulation of inhibitory cells or fibres in the CA1 subfield of the hippocampus yields a biphasic inhibitory postsynaptic potential (IPSP) in pyramidal cells, consisting of an early GABAA- and a late GABAB-mediated component. CA1 interneurons are a heterogeneous population of cells, which differ on the basis of their morphology, physiological properties, target selectivity onto principal cells, and network connectivity. Inhibitory synaptic circuitry appears to be specialized, since feedback inhibition may invoke only postsynaptic GABAA receptors, whereas feedforward inhibition may invoke both postsynaptic GABAA and GABAB receptors. In this review, we examine the evidence for and against the notion that distinct interneurons may be responsible for GABAA- and GABAB-mediated inhibition. Overall, the evidence suggests that (i) certain interneurons may generate solely GABAA inhibition, but the available data do not distinguish whether other interneurons mediate (ii) solely GABAB inhibition or (iii) a combination of both GABAA and GABAB.     

Enhanced bursts of IPSCs in dentate granule cells in mice with regionally inhibited long-term potentiation

Until recently, most studies on the synaptic-cellular basis of learning and memory concentrated on the activity-dependent changes occurring in principal cells such as hippocampal pyramidal cells and dentate granule cells. However, the ability of the inhibitory interneurons to regulate synaptic plasticity remains less understood. This study tested the hypothesis that the gamma-aminobutyric-acid (GABA)-mediated inhibitory neurotransmission is enhanced in mice that show no detectable long-term potentiation in the dentate gyrus in the absence of the GABAA receptor antagonist bicuculline. Patch clamp recordings were made from dentate granule cells in brain slices from wild-type and Thy-1 knockout (KO) mice. The frequency, amplitude and kinetics of miniature inhibitory postsynaptic currents (mIPSCs, generated by the action potential-independent release of GABA) was not different between animals. However, bursts of spontaneous IPSCs (sIPSCs, generated by both action potential-independent and -dependent GABA release) in KO mice were associated with larger synaptic charge transfers and increased durations. When pairs of IPSCs were evoked at varying intervals, the amplitude of the second response with respect to the first was significantly larger in KO animals. These results further support the concept that enhancement of interneuronal functions in cortical structures can have profound effects on the activity-dependent synaptic plasticity observed in principal cells.