Effects of GABAergic inhibition on neocortical long-term potentiation in the chronically prepared rat

Long-term potentiation (LTP) is a form of activity-dependent synaptic plasticity that is a candidate cellular mechanism for some forms of learning and memory. Although GABAergic synaptic inhibition plays a critical role in regulating of synaptic plasticity, there is still little known about the GABAergic modulation on LTP induction in chronic preparation. In the present study we examined the effect of GABA_A agonist, diazepam (DZM), and antagonist, picrotoxin (PTX) on the induction of LTP in the somatosensory cortex of freely moving rats for a long-term period. In adult rats a bipolar stimulating and recording electrode were implanted into corpus callusom and somatosensory cortex, respectively. Two weeks after the surgery, evoked field potential responses were recorded before, during (12 days), and after (1 month) induction period of LTP by high-frequency stimulation. The LTP characteristics were compared between control, DZM and PTX groups during the time course of recording in each rat. Administration of DZM prior to train, blocked the induction of neocortical LTP, while the PTX increased the development of LTP making the highest differential levels of LTP about 12 days after the initiation of LTP induction. Our findings suggest that the augmentation of LTP by PTX can be explained by an interaction between excitatory and inhibitory pathways. Suppression of neocortical inhibitory inputs by PTX causes enhancement in LTP induction. These results suggest that GABAergic system has an important role in synaptic plasticity and long-term modification of somatosensory cortex in freely moving rat.     

Presence of depolarization-induced suppression of inhibition in a fraction of GABAergic synaptic connections in rat neocortical cultures

Brief depolarization of postsynaptic neurons in hippocampus and cerebellum results in a transient depression of GABAergic inhibitory input, called “depolarization-induced suppression of inhibition” (DSI). We studied whether a similar phenomenon occurs in the rat neocortical neurons. Using patch-clamp technique in neocortical cell cultures, we examined the effects of a 5-second depolarization of postsynaptic neurons on evoked GABAergic inhibitory post-synaptic currents (IPSCs). We found that the depolarization evoked a suppression of IPSC amplitude in 6 out of 26 neuronal pairs tested. The suppression of IPSC amplitude lasted for ∼70 seconds and was accompanied by changes of paired-pulse ratio and IPSC coefficient of variation (CV), which is suggestive of a presynaptic mechanism. These results are in agreement with previous observations in hippocampal cell cultures and suggest that neocortical neurons express DSI. Published in Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 55, No. 5, pp. 581–585, September–October, 2005.     

Activation of the 5-HT6 receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus

The 5-HT₆ receptor is predominantly expressed in the CNS and has been implicated in the regulation of cognitive function. Antagonists of the 5-HT₆ receptor improve cognitive performance in a number of preclinical models and have recently been found to be effective in Alzheimer's disease patients. Systemic administration of 5-HT₆ antagonists increases the release of acetylcholine and glutamate in the frontal cortex and dorsal hippocampus. In contrast, the selective 5-HT₆ agonist, WAY-181187, can elicit robust increases in extracellular levels of GABA. The reported behavioral and neurochemical effects of 5-HT₆ receptor ligands raise the possibility that the 5-HT₆ receptor may modulate synaptic plasticity in the hippocampus. In the present study, selective pharmacological tools were employed to determine the effect of 5-HT₆ receptor activation on long-term potentiation (LTP) in brain slices containing area CA1 of the hippocampus. While having no effect on baseline synaptic transmission, the results demonstrate that the selective 5-HT₆ agonist, WAY-181187, attenuated LTP over a narrow dose range (100–300 nM). The increase in the slope of the field excitatory post synaptic potential (fEPSP) caused by theta burst stimulation in brain slices treated with the most efficacious dose of WAY-181187 (200 nM) was 80.1±4.0% of that observed in controls. This effect was dose-dependently blocked by the selective 5-HT₆ antagonist, SB-399885. WAY-181187 also increased the frequency of spontaneous GABA release in area CA1. As assessed by measuring and evaluating spontaneous inhibitory postsynaptic currents (sIPSCs), 200 nM WAY-181187 increased sIPSC frequency by 3.4±0.9 Hz. This increase in GABA sIPSCs was prevented by the selective 5-HT₆ antagonist SB-399885 (300 nM). Taken together, these results suggest that the 5-HT₆ receptor plays a role in the modulation of synaptic plasticity in hippocampal area CA1 and that the regulation of GABAergic interneuron activity may underlie the cognition enhancing effects of 5-HT₆ antagonists.     

Effects of an interleukin-1beta analogue [Lys-D-Pro-Thr], on incomplete cerebral ischemia-induced inhibition of long-term potentiation in rat hippocampal neurons in vivo

Although interleukin-1beta (IL-1beta) has recently been implicated in neuronal cell death in vitro and in vivo after global forebrain ischemia, the role of IL-1beta in the functional injuries, i.e. impairment of synaptic transmission, after cerebral ischemia that does not cause neuronal death in the nervous system remains unknown. To address this question, we investigated the effect of short-term incomplete ischemia without apparent neural death on hippocampal long-term potentiation (LTP) in anesthetized rats, and examined the possible role of IL-1beta as an intermediary in this effect. Short-term incomplete cerebral ischemia (10 min) was induced in halothane-anesthetized rats by bilaterally clamping the common carotid arteries. Four days after ischemia, functional injuries in neuronal transmission in the hippocampal formation were observed without significant changes in pathological studies such as neuronal cell death. The LTP elicited in both Shaffer-CA1 synapses and perforant path-dentate gyrus synapses was significantly inhibited by the short-term incomplete ischemia. This inhibition of LTP was blocked by IL-1beta tripeptide antagonist (Lys-D-Pro-Thr), suggesting that the inhibitory effect of mild ischemia on synaptic potentials and LTP may be mediated by the generation of IL-1beta. These findings have important implications for the role of IL-1beta in not only neuronal cell death but also functional injuries without cell loss, perhaps elicited by transient cerebral ischemia.     

Repeated blockade of GABAA receptors in the medial septal region induces epileptiform activity in the hippocampus

Changes in the activity of putative interneurons of the stratum oriens of the hippocampus and hippocampal EEG after the delivery of the GABAA receptor antagonist bicuculline (1.0nmol/1microl) to the medial septal region were investigated in awake rabbits. The injection of bicuculline produced a sharp increase in the firing rate in 94.3% of hippocampal cells. The effect of bicuculline on the neuronal theta rhythmicity depended on the number of injections. The first five daily infusions decreased the theta activity in 85.7% of cells. On the fourth to fifth experimental days paroxysmal discharges and 8-15Hz oscillations were recorded in the hippocampal EEG. Six to seven further daily bicuculline injections following a brief diminution of theta activity produced a sharp augmentation of theta oscillations in 78.9% of cells and provoked seizures. Immediately before seizures, stabilization of theta bursts and an increase in burst frequency was usually observed in putative interneurons. During seizures, neuronal rhythmic activity was either disordered and then turned into seizure discharges or was inhibited, partially or completely. In the hippocampal EEG, the power of theta rhythm before seizures usually strongly increased compared with controls. Injection of the GABAA agonist muscimol (30nmol/1microl) 15min before bicuculline infusion prevented the development of seizures. These findings suggest that the interplay between septal neurons via GABAA receptors is critical in the tuning of septal output signals that insure generation of natural theta rhythm as well as adequate functioning of the hippocampus.     

The EPSP-spike (E-S) component of long-term potentiation in the rat hippocampal slice is modulated by GABAergic but not cholinergic mechanisms

Long-term potentiation of synaptic efficacy (LTP) can be shown to consist of two components: a synaptic and an excitatory postsynaptic potential (EPSP)-spike (E-S) component. The E-S component is expressed as a leftward shift in the curve relating population spike amplitude as a function of EPSP slope. The participation of cholinergic and GABAergic processes in E-S potentiation was studied in field CA1 of rat hippocampal slices. Atropine, a muscarinic antagonist, did not prevent tetanus-induced E-S potentiation. The cholinergic agonist carbachol and the GABAA antagonist picrotoxin produced a leftward shift in the E-S relation; picrotoxin, but not carbachol, prevented the expression of tetanus-induced E-S potentiation. These observations indicate that an increase in the ratio of evoked excitation to inhibition and/or a reduction in tonic inhibition mediated by the activation of GABAA receptors contribute to E-S potentiation produced by high-frequency stimulation.     

Ionic mechanisms of GABA-induced long-term potentiation in the rat superior colliculus

GABA-induced excitation and long-term potentiation (LTPG) have been demonstrated recently in the superficial layers of the superior colliculus (SC). In other regions of the nervous system, GABA elicits excitatory responses via ionotropic GABA receptors under certain conditions. This excitation is proposed to be due to either a high neuronal chloride concentration favouring a depolarising chloride efflux, or to a bicarbonate efflux coupled to a chloride influx. The aim of this study was to characterise the mechanisms underlying excitation and prolonged increase in synaptic transmission induced by GABA in the SC. Extracellular field potentials were recorded from 1-month-old rat SC slices, and LTPG of these responses was evoked by application of 3 mM GABA. GABA-induced excitation and LTPG were significantly reduced by lowering the extracellular calcium concentration, but not by a decreased potassium concentration. Replacing the extracellular bicarbonate-buffered perfusion medium with a HEPES-buffered solution had no effect on LTPG but blocking the bicarbonate-generating enzyme carbonic anhydrase both intra- and extracellularly with ethoxyzolamide (50 microM) prevented LTPG. The chloride transport inhibitor bumetanide (50 microM) reduced but did not block LTPG. We therefore suggest that the contribution of the chloride equilibrium to LTPG is only of minor importance. The intracellular bicarbonate pool and related efflux provides the basis for the excitatory action of GABA, leading to a subsequent depolarisation and calcium influx through voltage-dependent calcium channels, thus causing long-lasting changes in synaptic transmission.     

Modulation of long-term potentiation in the rat hippocampus following cocaine self-administration

Long-lasting neuroadaptations that occur during drug use and remain after withdrawal are thought to contribute to the persisting and compulsive nature of drug addiction and relapse. At the molecular and cellular levels, mechanisms that have been implicated in the normal process of memory formation are increasingly being identified as potential contributors to the persistence of the addicted state. To investigate the effect of cocaine self-administration on synaptic plasticity, rats were allowed to self-administer 0.5 mg/kg/infusion cocaine or 0.9% NaCl during 90 min sessions for 15 consecutive days. These cocaine and saline self-administration subjects were then restricted to their home cages for 3, 30, or 100 days (3, 30, and 100 day cocaine/saline withdrawal groups) before the assessment of the induction and reversal of long-term potentiation (LTP) in the CA1 region of hippocampal slices. The magnitude of LTP was increased in the 3-day cocaine withdrawal group as compared with the 3-day saline withdrawal group, but this effect was short lived, as the 30-day cocaine and saline withdrawal groups exhibited similar LTP magnitudes. Interestingly, LTP was significantly decreased in the 100-day cocaine withdrawal group compared with the 100-day saline withdrawal group. These results support the hypothesis that the capacity for LTP is persistently altered after withdrawal from exposure to an addictive substance. In addition, this alteration can be differentially expressed such that depending upon the duration of the withdrawal period following the last drug exposure, LTP may be enhanced, unchanged, or suppressed.     

Modulation of long-term potentiation induction in the hippocampus by N-methyl-D-aspartate-mediated presynaptic inhibition.

We investigated mechanisms involved in the modulation of long-term potentiation by low concentrations of N-methyl-D-aspartate in the CA1 region of rat hippocampal slices. When applied for 5 min prior to and during tetanic stimulation, 1 microM N-methyl-D-aspartate inhibited long-term potentiation induction. Studies examining paired-pulse facilitation of non-N-methyl-D-aspartate receptor-mediated synaptic responses suggest that the effects of N-methyl-D-aspartate result in part from a presynaptic mechanism. This conclusion is supported by the observation that 1 microM N-methyl-D-aspartate failed to diminish N-methyl-D-aspartate receptor-mediated synaptic currents and that agents that enhance glutamate release, including high extracellular concentrations of calcium and an adenosine A1 receptor antagonist, overcome the long-term potentiation inhibition. Furthermore, the calcineurin inhibitors, FK-506 and cyclosporin A, as well as the phosphatase 1 and 2A inhibitor, okadaic acid, blocked the effects of N-methyl-D-aspartate on long-term potentiation suggesting a role for phosphatase activation in modulating the induction of long-term potentiation. These results show that the inhibition of long-term potentiation by untimely N-methyl-D-aspartate receptor activation is reversed by treatments that enhance glutamate release and suggest that adenosine release and diminished calcium influx during tetanic stimulation coupled with phosphatase activation contribute to the modulation of synaptic plasticity.     

Baclofen facilitates the development of long-term potentiation in the rat dentate gyrus

The effect of baclofen on the development of long-term potentiation (LTP) in the dentate gyrus was examined. Stimulus trains applied to the perforant path in the presence of baclofen produced significantly more potentiation of the perforant path-evoked response than did similar stimulation in control medium. In addition, baclofen enabled stimulus trains, ordinarily subthreshold for LTP induction, to produce LTP. These results demonstrate that GABAB receptor activation by baclofen makes repetitive stimulation more effective at producing LTP.     

Effects of experimental hypercapnia on hippocampal long-term potentiation in anesthetized rats

Neuronal voltage-dependent P/Q Ca2+ channels are genetically abnormal in many cases of familial hemiplegic migraine and possibly associated with the more common forms of migraine with and without aura. Besides the brain, these channels are found in motor nerve endings where they control stimulation-induced acetylcholine release. Using single fiber EMG recordings we were able to demonstrate subclinical abnormalities of neuromuscular transmission in a subgroup of patients suffering from migraine with aura. This could be related to genetic abnormalities of P/Q Ca2+ channels in certain patients suffering from migraine with aura, which needs to be explored by proper genetic analyses.     

Effects of experimental hypercapnia on hippocampal long-term potentiation in anesthetized rats

The effects of hypercapnia, which has been reported to impair consciousness, on the long-term potentiation of the population spike in the CA1 pyramidal cell of the hippocampus in anesthetized rats were studied. Experimental hypercapnemia was induced by inspired 13% CO₂ with 21% O₂. Arterial blood gas analysis after 80 min inspired 13% CO₂ showed pH 7.08±0.05, PCO₂=104.09±12.86 mmHg, PO₂=90.71±18.89 mmHg, BE −4.64±2.97 (mean±SD, n=18). Inspired 13% CO₂ reduced the amplitude of the population spike to 50% of the baseline. After delivery of tetanic stimulation (400 Hz, five bursts of eight pulses, inter-burst interval 1 s) population spike height was enhanced to pre-tetanic levels. Withdrawal of inspired CO₂ unmasked an increase in population spike amplitude. These findings suggest that acute retention of carbon dioxide, which is designated as pure hypercapnemia without hypoxemia, may suppress hippocampal synaptic transmission but not its plasticity.     

A role for c-Jun N-terminal kinase in the inhibition of long-term potentiation by interleukin-1beta and long-term depression in the rat dentate gyrus in vitro

Recent evidence has emphasised the importance of mitogen-activated protein kinase activation in the modulation of hippocampal synaptic plasticity. Whilst extracellular-regulated kinase activation is now regarded as a critical step in the induction of long-term potentiation (LTP), activation of p38 and c-Jun N-terminal kinase (JNK) is associated with its inhibition. Here, the effects of the novel JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-1 (SP600125) were investigated on the inhibition of LTP by cytokines interleukin-1beta, interleukin-18 and tumour necrosis factor-alpha in the dentate gyrus. Perfusion of SP600125 alone prior to tetanic stimulation of the medial perforant path did not significantly affect baseline synaptic transmission, post-tetanic potentiation or the magnitude of induced LTP. When SP600125 was perfused onto slices prior to application of cytokines, this resulted in a complete reversal of the cytokine-mediated inhibition of LTP. Moreover, the magnitude of LTP attained in these slices was significantly greater than that obtained in vehicle control slices. Next, we investigated the effects of the JNK inhibitor on the impairment of pharmacologically isolated N-methyl-D-aspartate receptor-mediated potentials (NMDA-EPSPs) by interleukin-18. Whilst not affecting baseline amplitude when perfused alone, prior perfusion of SP600125 alleviated the depressive effect of interleukin-18 on NMDA-EPSPs. Finally, we examined the possibility of JNK involvement in the induction of long-term depression (LTD) in the dentate gyrus. Perfusion of SP600125 prior to low-frequency stimulation of the perforant path resulted in a significant attenuation of induced LTD, which suggests that JNK activation is a critical mediator of LTD in the dentate gyrus.These results directly implicate, for the first time, differential activation of JNK in the modulation of distinct forms of hippocampal synaptic plasticity. Whereas acute over-activation of JNK by pathophysiological concentrations of cytokines is detrimental to LTP, physiologic activation of JNK appears necessary for the induction of LTD.     

Thapsigargin blocks the induction of long-term potentiation in rat hippocampal slices.

Experiments were performed to investigate whether intact intracellular Ca2+ pools are necessary for long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. Thapsigargin (1 microM), which depletes most intracellular Ca2+ pools by blocking ATP-dependent Ca2+ uptake into intracellular compartments, blocked the induction but not the expression of LTP. Thapsigargin had no effect on synaptic transmission or on responses mediated by N-methyl-D-aspartate (NMDA) receptor activation. These data suggest that Ca2+ release from intracellular stores is required for the induction of LTP.     

Mechanisms underlying the inhibition of long-term potentiation by preconditioning stimulation in the hippocampus in vitro

We have investigated the mechanisms underlying a form of metaplasticity, namely the inhibition by preconditioning stimulation of high frequency stimulation (HFS)-induced long-term potentiation (LTP) in the medial perforant path of the dentate gyrus. Preconditioning stimulation (weak 50 Hz) was found to inhibit subsequent LTP induction if applied 10-20 min, but not 2 or 45 min, prior to the HFS. Preconditioning stimulation in the form of low frequency stimulation did not block LTP induction. The inhibition of LTP was not caused by a reduction in N-methyl-D-aspartate receptor (NMDAR) transmission, as the preconditioning stimulation did not reduce isolated NMDAR-mediated EPSPs. The involvement of group I and group II metabotropic glutamate receptor (mGluR) activation in the inhibition of LTP was demonstrated by experiments in which the inhibition of LTP by the preconditioning stimulation was prevented by the presence of antagonists of group I or group II mGluR during the preconditioning stimulation. Moreover, group I and group II mGluR agonists directly inhibited subsequent LTP induction. The involvement of NMDAR in the preconditioning stimulation was shown by the ability of an NMDAR antagonist to prevent the inhibition of LTP by the preconditioning stimulation. The preconditioning inhibition of LTP induction was shown by the use of kinase inhibitors to involve activation of PKC and p38 MAP kinase, but not p42 MAP kinase or tyrosine kinase. We conclude that the preconditioning inhibition of LTP induction is a complex process which involves activation of NMDAR, group I and group II mGluR, and intracellular cascades activating PKC and p38 MAP kinase.     

Release of proteins during long-term potentiation in the hippocampus of the anaesthetized rat

Using a push-pull device, the release of endogenous proteins in the extracellular space was investigated in the CA1 region of the hippocampus of anaesthetized rats. With low-frequency stimulation of the Schaffer collaterals, there was a relatively stable release of 5 proteins (64, 54, 48, 45 and 16 kDa). A train of high-frequency stimulation produced a long-lasting enhancement of the negative field EPSP and a delayed (90-120 min) enhancement of the release of these proteins. An additional 19 kDa protein was present only 90 min after the train. These observations raise the possibility that release of proteins might be involved in the maintenance of LTP.     

In vivo recordings of long-term potentiation and long-term depression in the dentate gyrus of the neonatal rat

Previous in vitro studies demonstrated that long-term potentiation (LTP) could be elicited at medial perforant path (MPP) synapses onto hippocampal granule cells in slices from 7-day-old rats. In contrast, in vivo studies suggested that LTP at perforant path synapses could not be induced until at least days 9 or 10 and then in only a small percentage of animals. Because several characteristics of the oldest granule cells are adult-like on day 7, we re-examined the possibility of eliciting LTP in 7-day-old rats in vivo. We also recorded from 8- and 9-day-old rats to further elucidate the occurrence and magnitude of LTP in neonates. With halothane anesthesia, all animals in each age group exhibited synaptic plasticity of the excitatory postsynaptic potential following high-frequency stimulation of the MPP. In 7-day-old rats, LTP was elicited in 40% of the animals and had an average magnitude of 143%. Long-term depression (LTD) alone (magnitude of 84%) was induced in 40% of the animals, while short-term potentiation (STP) alone (magnitude of 123%) was induced in 10%. STP followed by LTD was elicited in the remaining 10%. Data were similar for all ages combined. In addition, the N-methyl-d-aspartate (NMDA) antagonist (R,S)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked the occurrence of LTP at each age and doubled the percentage of animals expressing LTD alone for all ages combined. These results demonstrate that tetanic stimulation can elicit LTP or LTD at MPP synapses in 7-day-old rats, supporting our premise that at least a portion of the dentate gyrus is functional at this early age.     

4-Aminopyridine-mediated increase in long-term potentiation in CA1 of the rat hippocampus

The effect of 4-aminopyridine (4-AP) on long-term potentiation (LTP) was studied in the hippocampal slice preparation of the rat. Field excitatory postsynaptic potentials (EPSPs) were recorded and evoked in the stratum radiatum of the CA1. Both the low frequency EPSP and LTP of the EPSP were significantly increased by treatment with 4-AP. These effects were inhibited by increasing the magnesium concentration from 1 to 4 mM. Pretreatment with 20 microM DL-2-amino-5-phosphonovalerate antagonized only the increase in LTP produced by 4-AP. It is suggested that 4-AP enhances Ca influx either pre- or postsynaptically and thereby increases LTP.     

Thyrotropin-releasing hormone inhibits long-term potentiation in synaptic systems of rat hippocampus

The effects of thyrotropin-releasing hormone (TRH) on long-term potentiation of field responses in mossy fibers—CA3 and Shaffer collaterals—CA1 synaptic systems were studied on rat hippocampal slices. Incubation with micromolar concentrations of TRH inhibited the development of long-term potentiation in both synaptic systems. It is suggested that this phenomenon underlies the antiamnesic effect of TRH. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 12, pp. 690–693, December, 1999