Population Spike Responses Research Articles

After-effects of repetitive transcranial magnetic stimulation with parameter dependence on long-term potentiation-like plasticity and object recognition memory in rats.

To investigate the after-effects of 25-Hz repetitive transcranial magnetic stimulation (rTMS) at 60, 100, and 120% resting motor threshold (rMT) on long-term potentiation (LTP) in the rat hippocampus, to clarify the intensity dependence of rTMS, and to determine whether it simultaneously affects learning and memory ability. Five rats were randomly selected from 70 male Wistar rats, and evoked rMT potentials were recorded in response to magnetic stimulation. The remaining 65 rats were randomly assigned to five groups (n = 13), including sham rTMS, 1 Hz 100% rMT, and 25 Hz rTMS groups with 3 subgroups of 60% rMT, 100% rMT, and 120% rMT. Five rats in each group were anesthetized and induced by a priming TMS-test design for population spike (PS) response of the perforant path-dentate gyrus in the hippocampus; the remaining eight rats in each group were evaluated for object recognition memory in the novel object recognition (NOR) task after the different rTMS protocols. Forty-five percent (approximately 1.03 T) of the magnetic stimulator output was confirmed as rMT in the biceps femoris muscle. The PS ratio was ranked as follows: 25 Hz 100% rMT (267.78 ± 25.71%) > sham rTMS (182 ± 9.4%) >1 Hz 100% rMT (102.69 ± 6.64%) > 25 Hz 120% rMT (98 ± 11.3%) > 25 Hz 60% rMT (36 ± 8.5%). Significant differences were observed between the groups, except for the difference between the 25 Hz 120% rMT and the 1 Hz 100% rMT groups (p = 0.446). LTP was successfully induced over the 60-min recording period only in the sham rTMS and 25 Hz 100% rMT groups. Moreover, these two groups spent more time exploring a novel object than a familiar object during the NOR task (p < 0.001), suggesting long-term recognition memory retention. In the between-group analysis of the discrimination index, the following ranking was observed: 25 Hz 100% rMT (0.812 ± 0.158) > sham rTMS (0.653 ± 0.111) > 25 Hz 120% rMT (0.583 ± 0.216) >1 Hz 100% rMT (0.581 ± 0.145) > 25 Hz 60% rMT (0.532 ± 0.220). The after-effect of 25-Hz rTMS was dependent on stimulus intensity and provided an inverted (V-shaped) bidirectional modulation on hippocampal plasticity that involved two forms of metaplasticity. Furthermore, the effects on the recognition memory ability were positively correlated with those on LTP induction in the hippocampus in vivo.

Noise Enhanced Signaling in STDP Driven Spiking-Neuron Network

Population spike signaling is widely observed both in intact brain and neuronal cultures. Experimental evidence suggests that a locally applied electrical stimulus can shape the network architecture and thus the neuronal response. However, there is no clue on how this process can be controlled. Here we study a realistic model of a culture of cortical-like neurons with spike timing dependent plasticity. We show that a stimulus applied at a corner of the culture can rebuild synaptic couplings. Then the network eventually switches from a turbulent-like asynchronous spiking to an ordered population spike signaling mode. The structural analysis shows that the stimulus potentiates centrifugal couplings, which promotes spiking waves traveling outwards the stimulus location. This phenomenon can be catalyzed by noise of an intermediate strength. We predict that matured cultures with high connectivity are more susceptible to reconfiguration and generation of a population spike response than young cultures with low connectivity. We also report on an intermittent synchronization causing switches between two quasi-stable states: generation of time-locked population spikes and turbulent spiking. In the turbulent mode the stimulus excites patches of spiking activity randomly traveling in the network. Such a regime can be implemented through a large scale looping of couplings backwards to the stimulus location. We anticipate that the robust mechanisms of shaping the network architecture discussed here can also be effective in more complex preparations and studies of the relationship between network structure and function.

EPV 14. Non-invasive single-trial detection of human population spike responses in somatosensory evoked potentials in a realistic clinical setting

Introduction High-frequency EEG oscillations ( ≈ 600 Hz; HFO) evoked by median nerve stimulation and recorded above the human somatosensory cortex are non-invasive correlates of cortical population spikes. Recently, it was shown that spatiotemporal filtering and multivariate classification enables single-trial HFO detection using 29-channel low-impedance ( Ω ) low-noise EEG in an electromagnetically shielded recording chamber. It is an open question, whether this can be achieved in a realistic clinical setting. Methods With a custom-built CE-certified low-noise EEG amplifier, median nerve SEPs were recorded in 10 healthy subjects using 8 electrodes (impedances ≈ 1 k Ω ) in a standard unshielded hospital environment. After band-pass filtering (500–900 Hz), a subset of the trials (N = 2000) was used to train the two-step single-trial HFO detector, which is composed of spatiotemporal filter optimization and nonlinear classification. The performance of the algorithm was assessed using an independent set of additional trials (N = 5200). Results In the present group of 10 subjects, on average the algorithm detected evoked HFOs in 64.9% of the single trials in the correct latency window (around ≈ 20 ms) with a positive predictive value (PPV) of 61.9%. Notably, in several subjects with a higher signal-plus-noise-to-noise ratio (SNNR), detection rate (DR) and PPV were above 80% (peak values: SNNR = 2.0, DR = 95.2%, PPV = 98.5%). Conclusions A non-invasive single-trial detection of human population spike responses in somatosensory evoked potentials can be achieved also in a realistic unshielded clinical setting. The increase in sensitivity brought about by combined hardware and algorithmic improvements enables the analysis of single-trial variability and might be extended also to pathological components, such as the non-invasive detection of epileptic neocortical high-frequency oscillations.

Non-invasive single-trial detection of variable population spike responses in human somatosensory evoked potentials

ObjectiveSomatosensory evoked potentials (SEPs) around 600Hz (‘σ-bursts’) are correlates of cortical population spikes. Recently, single-trial σ-bursts were detected in human scalp EEG using 29-channel low-noise recordings in an electromagnetically shielded room. To achieve clinical applicability, this study aimed to establish a protocol using only 8 EEG channels in an unshielded environment and to quantify the variability of σ-bursts. MethodsMedian nerve SEPs were recorded in 10 healthy subjects using a custom-built low-noise EEG amplifier. A detection algorithm for single-trial σ-bursts was trained as combination of spatio-temporal filters and a non-linear classifier. The single-trial responses were probed for the presence of significant increases of amplitude and variability. ResultsSingle-trial σ-burst detection succeeded with Detection Rates and Positive Predictive Values above 80% in subjects with high SNR. A significant inter-trial variability in the amplitudes of early low-frequency SEPs and σ-bursts could be demonstrated. ConclusionsSingle-trial σ-bursts can be detected on scalp-EEG using only 8 EEG channels in an electromagnetically disturbed environment. The combination of dedicated hardware and detection algorithms allows quantifying and describing their variability. SignificanceThe variability of population spikes in the human somatosensory cortex can be traced non-invasively in a clinical setting.

Long-term depression is differentially expressed in distinct lamina of hippocampal CA1 dendrites.

Information storage in CA1 hippocampal pyramidal neurons is compartmentalized in proximal vs. distal apical dendrites, cell bodies, and basal dendrites. This compartmentalization is thought to be essential for synaptic integration. Differences in the expression of long-term potentiation (LTP) in each of these compartments have been described, but less is known regarding potential differences in long-term depression (LTD). Here, to directly compare LTD expression in each compartment and to bypass possible differences in input-specificity and stimulation of presynaptic inputs, we used global application of NMDA to induce LTD. We then examined LTD expression in each dendritic sub-region—proximal and distal apical, and basal dendrites—and in cell bodies. Interestingly, we found that distal apical dendrites exhibited the greatest magnitude of LTD of all areas tested and this LTD was maintained, whereas LTD in proximal apical dendrites was not maintained. In basal dendrites, LTD was also maintained, but the magnitude of LTD was less than in distal apical dendrites. Blockade of inhibition blocked LTD maintenance in both distal apical and basal dendrites. Population spikes recorded from the cell body layer correlated with apical dendrite field EPSP (fEPSP), where LTD was maintained in distal dendrites and decayed in proximal dendrites. On the other hand, LTD of basal dendrite fEPSPs was maintained but population spike responses were not. Thus E-S coupling was distinct in basal and apical dendrites. Our data demonstrate cell autonomous differential information processing in somas and dendritic sub-regions of CA1 pyramidal neurons in the hippocampus, where LTD expression is intrinsic to distinct dendritic regions, and does not depend on the nature of stimulation and input specificity.

Recording human cortical population spikes non-invasively – An EEG tutorial

BackgroundNon-invasively recorded somatosensory high-frequency oscillations (sHFOs) evoked by electric nerve stimulation are markers of human cortical population spikes. Previously, their analysis was based on massive averaging of EEG responses. Advanced neurotechnology and optimized off-line analysis can enhance the signal-to-noise ratio of sHFOs, eventually enabling single-trial analysis. MethodsThe rationale for developing dedicated low-noise EEG technology for sHFOs is unfolded. Detailed recording procedures and tailored analysis principles are explained step-by-step. Source codes in Matlab and Python are provided as supplementary material online. ResultsCombining synergistic hardware and analysis improvements, evoked sHFOs at around 600Hz (‘σ-bursts’) can be studied in single-trials. Additionally, optimized spatial filters increase the signal-to-noise ratio of components at about 1kHz (‘κ-bursts’) enabling their detection in non-invasive surface EEG. ConclusionssHFOs offer a unique possibility to record evoked human cortical population spikes non-invasively. The experimental approaches and algorithms presented here enable also non-specialized EEG laboratories to combine measurements of conventional low-frequency EEG with the analysis of concomitant cortical population spike responses.

High-frequency EEG covaries with spike burst patterns detected in cortical neurons

Invasive microelectrode recordings measure neuronal spikes, which are commonly considered inaccessible through standard surface electroencephalogram (EEG). Yet high-frequency EEG potentials (hf-EEG, f > 400 Hz) found in somatosensory evoked potentials of primates may reflect the mean population spike responses of coactivated cortical neurons. Since cortical responses to electrical nerve stimulation vary strongly from trial to trial, we investigated whether the hf-EEG signal can also echo single-trial variability observed at the single-unit level. We recorded extracellular single-unit activity in the primary somatosensory cortex of behaving macaque monkeys and identified variable spike burst responses following peripheral stimulation. Each of these responses was classified according to the timing of its spike constituents, conforming to one of a discrete set of spike patterns. We here show that these spike patterns are accompanied by variations in the concomitant epidural hf-EEG. These variations cannot be explained by fluctuating stimulus efficacy, suggesting that they were generated within the thalamocortical network. As high-frequency EEG signals can also be reliably recorded from the scalp of human subjects, they may provide a noninvasive window on fluctuating cortical spike activity in humans.

Nonlinear Dynamic Model of CA1 Short-Term Plasticity using Random Impulse Train Stimulation

A comprehensive, quantitative description of the nonlinear dynamic characteristics of the short-term plasticity (STP) in the CA1 hippocampal region is presented. It is based on the Volterra-Poisson modeling approach using random impulse train (RIT) stimuli. In vitro hippocampal slice preparations were used from adult rats. RIT stimuli were applied at the Schaffer collaterals and population spike responses were recorded at the CA1 cell body layer. The computed STP descriptors that capture the nonlinear dynamics of the underlying STP mechanisms were the Volterra-Poisson kernels. The kernels quantified the presence of facilitatory and inhibitory STP behavior in magnitude and duration. A third order Volterra-Poisson STP model was introduced that accurately predicted in-sample and out-of-sample system responses. The proposed model could also accurately predict impulse pair and short impulse train system responses.

Different anticonvulsive effects of hesperidin and its aglycone hesperetin on electrical activity in the rat hippocampus in-vitro

This study investigated the possibility that hesperidin or hesperetin might interact directly with brain matter in a physiological manner. The effects of both compounds were followed in the in-vitro hippocampus preparation by continuous superfusion in a concentration-dependent manner in the presence of single stimuli and theta-burst stimulation of the Schaffer Collaterals. Hesperidin increased the population spike response at a concentration up to 10 microM, especially after induction of long-term potentiation, but attenuated it significantly at higher concentrations of up to 60 microM. Hesperetin only attenuated the response within the same concentration range. Modulation of the pyramidal cell response in the presence of tetraethylammonium (TEA) and pentylentetrazol on one hand and 4-aminopyridine (4-AP) and bicuculline on the other was influenced in a different way. Whereas hesperidin attenuated the response to 4-AP and bicuculline but not to TEA or pentylentetrazol, hesperetin was able to attenuate the response to TEA and pentylentetrazol, but not to 4AP or bicuculline. This feature was reproduced and confirmed ex-vivo after repetitive administration of hesperidin and hesperetin in-vivo for one week (500 mg kg(-1) orally) before in-vitro testing against the challenging effects of 4-AP and TEA. Since the action of hesperidin was sensitive to the presence of iberiotoxin, the involvement of a large conductance calcium-dependent potassium channel might be assumed. In summary, the results provide the possibility for use of both compounds to control pathophysiological disturbances of brain excitability in drug abuse, migraine and epilepsy.

Dopamine-Mediated Disinhibition in the CA1 Region of Rat Hippocampus via D3 Receptor Activation

The hippocampal formation is thought to contribute to both addictive behaviors and to psychotic disorders, and the actions of the neurotransmitter dopamine are intimately involved with these disease states. We have used both whole-cell and extracellular recording techniques in hippocampal slices to investigate the actions of both cocaine and dopamine receptor agonists in the CA1 region. In the presence of cocaine (10 microM), endogenously released dopamine decreased monosynaptic inhibitory postsynaptic currents (IPSCs) evoked from stratum radiatum but not from stratum oriens. This effect of cocaine was not blocked by the D(1/5) antagonist SCH 23390 ({R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine}) (3 microM), whereas several D(2)-like dopamine receptor antagonists prevented the cocaine-induced decrease in the IPSC. The most selective of the effective antagonists tested was the D(3) antagonist, U 99194 ({5,6-dimethoxy-indan-2-yl dipropylamine}) maleate (1 microM). An exogenously applied D(3)-selective dopamine receptor agonist, PD 128907 ({(+)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano-[4,3-b]-1,4-oxazin-9-ol}) (1 microM), also significantly inhibited the IPSC, providing further evidence that the activation of the D(3) subtype of dopamine receptor by endogenously released dopamine can modulate inhibition in the CA1 region. This disinhibitory action on pyramidal cells also increased synaptic excitability following Schaffer collateral stimulation, as demonstrated by either a decrease in paired-pulse inhibition of the population spike response or by an increase in the excitatory component of the mixed synaptic response evoked from stratum radiatum. These actions indicate that the activation of D(3) receptors by endogenously released dopamine, especially under conditions of transporter blockade, may significantly impact the processing of synaptic information through the stratum radiatum layer of the hippocampus.

Detecting CA1 short-term plasticity variations associated with changes in stimulus intensity and extracellular medium composition

Changes in STP characteristics in the CA1 hippocampal region have been studied using the Volterra–Poisson modeling approach. Random impulse trains stimuli were applied to the Schaffer collaterals of the CA1 hippocampus in vitro and population spike responses were recorded at the pyramidal cell body layer. The computed Volterra–Poisson kernels captured the nonlinear dynamics associated with the mechanisms underlying STP by identifying quantitatively the magnitude and the duration of facilitatory and depressive behavior. The variations in STP characteristics secondary to changes in the stimulus intensity level and the addition of chemicals to the in vitro preparation were reflected in the differences of the calculated Volterra–Poisson kernels. Increasing the stimulus intensity caused an increase in the value of the first-order kernel (mean of the population spike amplitude) and decreased the peak facilitation of the second-order kernel. Picrotoxin caused an increase in the mean of PS amplitude, an increase in peak facilitation value, and an increase in the magnitude of the depressive phase of the second-order kernel. Decreasing the extracellular calcium concentration caused a decrease in the value of the first-order kernel and increased the peak facilitation value of the second-order kernel. Finally, the ability of the Volterra–Poisson modeling approach to track STP changes was confirmed through the low normalized mean square error associated with the prediction of in-sample and out-of-sample responses.

Suppression of Hippocampal Slice Excitability by 2-, 3-, and 4-Methylpyridine

The present study assessed the effects of 2-, 3-, and 4-methylpyridine on rat hippocampal slice excitability. Tests of excitatory and inhibitory systems in area CA1 of the hippocampal slice were conducted over a period of 3 h postexposure. Following exposures of 100 μM 2-, 3-, or 4-methylpyridine, evoked population excitatory postsynaptic potential and population spike responses recorded in the cell body field of hippocampal area CA1 were slowly suppressed over the course of 3 h, whereas no effects on local inhibitory processes or latency of evoked responses were detected. No significant differences were observed between agents.

Dentate granule cell function after neonatal treatment with parachloroamphetamine or 5,7-dihydroxytryptamine

In vitro, extracellular electrophysiological recording was used to test granule cell responses in P60 rats after neonatal PCA and 5,7-DHT. Granule cell population EPSP and spike responses were in the normal range for both PCA and 5,7-DHT groups. However, the degree of paired pulse facilitation was reduced in both of these groups relative to control, reflecting a diminished synaptic drive. Synaptic potentiation in the 5,7-DHT group was not different from control, but was significantly reduced in slices from PCA-treated rats.

Long-Term Effects of Transcranial Magnetic Stimulation on Hippocampal Reactivity to Afferent Stimulation

Transcranial magnetic stimulation (TMS) has become a promising treatment of affective disorders in humans, yet the neuronal basis of its long-lasting effects in the brain is still unknown. We studied acute and lasting effects of TMS on reactivity of the rat hippocampus to stimulation of the perforant path. Application of TMS to the brain of the anesthetized rat caused a dose-dependent transient increase in population spike (PS) response of the dentate gyrus to perforant path stimulation. In addition, TMS caused a marked decrease in inhibition and an increase in paired-pulse potentiation of reactivity to stimulation of the perforant path. Also, TMS suppressed the ability of fenfluramine (FFA), a serotonin releaser, to potentiate PS response to perforant path stimulation. Chronic TMS did not affect single population spikes but caused an increase in paired-pulse potentiation, which was still evident 3 weeks after the last of seven daily TMS treatments. After chronic TMS, FFA was ineffective in enhancing reactivity to perforant path stimulation, probably because it lost the ability to release serotonin. In addition, the beta adrenergic receptor agonist isoproterenol, which caused an increase in PS in the control rats, failed to do so in the TMS-treated rats. These results indicate that TMS produces a long-term reduction in efficacy of central modulatory systems.

Age-dependent, steroid-specific effects of oestrogen on long-term potentiation in rat hippocampal slices.

1. Long-term potentiation (LTP) of hippocampal population spike responses and excitatory postsynaptic potentials (EPSPs) from area CA1 stratum pyramidale was induced in slices of rat hippocampus maintained in vitro following brief high-frequency stimulation (HFS) of the Schaffer collateral-commissural pathway. When administered to slices prior to HFS, 17beta-oestradiol (OE2), at a concentration as low as 0.1 nM, suppressed the magnitude of the resultant HFS-induced potentiation in slices from prepubertal animals (3 and 4 weeks old) of both sexes. 2. OE2 did not suppress the induction of LTP in slices taken from the hippocampus of adult animals of either sex. 3. There was no similar suppressant effect of 17alpha-oestradiol (OE1), progesterone (PRG) or testosterone (TST) on LTP in the young animals, even at a concentration 100 times greater than was effective for OE2. 4. The anti-oestrogen compound tamoxifen (TMX; 1.0 and 10.0 microM), which acts principally at intracellular binding sites within the nucleus, was without effect in diminishing the suppressant effect of OE2 on LTP in slices from young animals. 5. The LTP observed in slices from both 3-week-old and adult rats was AP5 sensitive and thus was shown to be dependent on activation of NMDA receptors. Results from whole-cell recording experiments suggested that OE2 caused the LTP-suppressant effect through an action on NMDA-mediated currents. 6. These data suggest an age-dependent and possibly a surface membrane receptor-mediated role for oestrogens in modulating the efficacy of input-output properties of CA1 neurones produced by HFS during a critical period in development.

Correlation between cannabinoid mediated effects on paired pulse depression and induction of long term potentiation in the rat hippocampal slice

Cannabinoids cause an increase in synaptic transmission via γ-aminobutyric acid (GABA) receptors and this may be the mechanism by which activation of CB1 receptors blocks the induction of long-term potentiation (LTP). To test this hypothesis, we used paired pulse depression (PPD) of CA1 population spike responses recorded in the rat hippocampal slice as an index of GABA-ergic feedback inhibition, to establish whether the effects of a stereoselective CB1 receptor agonist on GABA-ergic transmission and LTP were correlated. The active isomer, WIN55 212-2, blocked the induction of LTP and suppressed PPD over the concentration range 250 nM–5 μM, whereas the inactive isomer, WIN55 212-3, was inactive at 5 μM. The effects of 5 μM WIN55 212-2 on both LTP and PPD were completely blocked by the CB1 receptor antagonist SR141716A (5 μM). The results show that the effects are correlated in that both suppression of PPD and blockade of induction of LTP are probably mediated by CB1 receptors. However, the suppression in PPD suggests that WIN55 212-2 caused a decrease in GABA-ergic feedback transmission which would be expected to facilitate, rather than block, the induction of LTP. We therefore conclude that the blockade of LTP by cannabinoids is not via upregulation of GABA-ergic synaptic transmission.

Serotonin 5-HT1A Receptors Modulate Hippocampal Reactivity to Afferent Stimulation

Hippocampal dentate gyrus reactivity to perforant path (PP) stimulation in the anesthetized rat was enhanced after systemic administration of the serotonin-releasing drug fenfluramine (FFA). This effect of FFA was mimicked by local application of the drug via the recording pipette, indicating that the effect of FFA is mediated by release of serotonin from intrahippocampal serotonergic terminals. The 5-HT1a antagonist NAN-190 and the 5-HT1b agonist CGS-12066-B, applied both systemically and locally, blocked the effect of FFA. This blocking action was not shared by the 5-HT2-4 receptor agonists or antagonists tested. The 5-HT1a receptor agonist 8-OH-DPAT, applied systemically, caused a marked reduction in population spike responses to PP stimulation, whereas an opposite effect was produced by local application of this drug. The effect of peripheral application of 8-OH-DPAT was blocked by depletion of serotonin. The local effect of FFA was blocked by a reducing neurotransmitter release with a pipette containing 10 mM Mg2+. Finally, local application of the GABA antagonist picrotoxin also enhanced population spike response to PP stimulation, and the effects of picrotoxin and FFA occluded. These results indicate that serotonin released from terminals in the hippocampus activates a 5-HT1a receptor on interneurons that suppresses their activity and thus enhances dentate granular cell population spike response to PP stimulation.

The effect of propofol on ca1 pyramidal cell excitability and gaba a-mediated inhibition in the rat hippocampal slice

An in vitro paired-pulse orthodromic stimulation technique was used to examine the effects of propofol on excitatory afferent terminals, CA1 pyramidal cells and recurrent collateral evoked inhibition in the rat hippocampal slice. Hippocampal slices 400 um thick were perfused with oxygenated artificial cerebrospinal fluid, and electrodes were placed in the CA1 region to record extracellular field population spike (PS) or excitatory postsynaptic potential (EPSP) responses to stimulation of Schaffer collateral/commissural fibers. Gamma-aminobutyric acid (GABA)-mediated recurrent inhibition was measured using a paired-pulse technique. The major effect of propofol (7–28 μM) was a dose and time dependent increase in the intensity and duration of GABA-mediated inhibition. This propofol effect could be rapidly and completely reversed by exposure to known GABA A antagonists, including picrotoxin, bicuculline and pentylenetetrazol. It was also reversed by the chloride channel antagonist, 4,4′-diisothiocyanostilbene-2,2′-disulfonicacid (DIDS). It was not antagonized by central (flumazenil) or peripheral (PK11195) benzodiazepire antagonists. Reversal of endogenous inhibition was also noted with the antagonists picrotoxin and pentylenetetrazol. Input/output curves constructed using stimulus propofol caused only a small enhancement of EPSPs at higher stimulus intensities but had no effect on PS amplitudes. These studies are consistent with propofol having a GABA A-chloride channel mechanism causing its effect on recurrent collateral evoked inhibition in the rat hippocampal slice.

Persistent dentate granule cell hyperexcitability after neonatal infection with lymphocytic choriomeningitis virus

Infection of neonatal Lewis rats with lymphocytic choriomeningitis virus (LCMV) produces distinct retinal, cerebellar, and hippocampal neuropathology. To understand the neurophysiological consequences of LCMV-induced hippocampal pathology, we studied evoked monosynaptic potentials and electro-encephalographic (EEG) activity in the dentate gyrus and CA1 and CA3 subfields of the hippocampus in vivo. Lewis rats were inoculated intracerebrally with LCMV at postnatal day 4. In rats studied 84-107 d postinfection, virus was cleared from the dentate gyrus and the number of dentate granule cells was decreased by 70%. No viral antigen or cell loss was apparent in CA1 or CA3. The hippocampal EEG of LCMV-infected rats 84-102 d postinfection was dominated by continuous theta. Although evoked potentials elicited in CA1 and CA3 by monosynaptic afferent stimulation revealed no differences between sham- and LCMV-infected rats, there was a site-specific dissociation of synaptic [population excitatory postsynaptic potential (pEPSP)] and cellular (population spike) responses and a suppression of GABA-mediated recurrent inhibition in the dentate gyrus of LCMV-infected rats. These findings indicate that GABA-mediated inhibition was markedly decreased in LCMV-infected rats. In support of this, parvalbumin-immunoreactive cell bodies and neuronal processes were decreased in LCMV-infected rats, suggesting that a subpopulation of GABA interneurons was affected. These findings indicate that abnormalities in synaptic function persist after clearance of infectious virus from the central nervous system and suggest that decreased inhibition subsequent to pathological sequence in a subpopulation of GABA interneurons may be implicated in the hyperexcitability of dentate granule cells.

2-Hydroxy-saclofen causes a phaclofen-reversible reduction in population spike amplitude in the rat hippocampal slice

2-Hydroxy-saclofen is known to be active at GABA B receptors in the mammalian central nervous system, and we have investigated its effects on synaptic transmission in the rat hippocampal slice preparation. Orthodromic stimuli were applied to the stratum radiatum, and population spike responses from the CA1 pyramidal cell layer were recorded extracellularly. A second, identical stimulus was applied at a variable interpulse interval (IPI) after the initial conditioning stimulus. GABAergic synaptic inhibition was observed as a decrease in the spike amplitude of the second response compared to the first. Both the GABA B receptor antagonist phaclofen (1 mM) and 2-hydroxy-saclofen (200 μM) prevented a slow phase of inhibition for IPIs of 200–400 ms. However, these agents differed markedly in their effects on overall synaptic transmission. Phaclofen had no effect on the amplitude of the initial conditioning spike amplitude, whereas 2-hydroxy-saclofen reduced it significantly, in a manner similar to baclofen (1 μM). The direct actions of 2-hydroxy-saclofen were unexpected for a pure antagonist of GABA B receptors, but could be prevented by the co-administration of phaclofen (1 mM), but not bicuculline (1 μM). Reduction in conditioning spike amplitude due to antagonism of GABA B autoreceptors on inhibitory interneurones and subsequent enhancement of GABA A tonic inhibition would have been blocked by bicuculline. The blockade of the 2-hydroxy-saclofen effect by phaclofen implies a GABA B receptor partial agonist action. The possible sites of this action are discussed.