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PubMed1999

Promotion of forskolin-induced long-term potentiation of synaptic transmission by caffeine in area CA1 of the rat hippocampus.

Caffeine which is present in soft drinks has been shown to increase alertness and allays drowsiness and fatigue. The aim of this study is to investigate whether caffeine could produce a long-term effect on the synaptic transmission using extracellular recording technique in the hippocampal slices. Bath application of caffeine (100 microM) reversibly increased the slope of field excitatory postsynaptic potential (fEPSP). Forskolin (25 microM) by its own did not affect the fEPSP significantly. However, in the presence of caffeine, forskolin induced a long-term potentiation (LTP) of fEPSP. Enprofylline which has been shown to exhibit some actions like caffeine but with a low adenosine antagonistic potency did not affect the normal synaptic transmission or the effect of forskolin at a lower concentration (10 microM). However, when the concentrations were increased to 20 and 50 microM, enprofylline significantly enhanced the fEPSP slope and promoted forskolin-induced LTP. The parallel increase of fEPSP and promotion of LTP observed with enprofylline suggests that adenosine A1 antagonism is the primary mechanism behind caffeine's effect. This hypothesis was further strengthened by the finding that promotion of forskolin-induced LTP was mimicked by the non-xanthine adenosine antagonist 9-chloro-2-(furyl)[1,2,4]triazolo [1,5-c]quinazolin-5-amine (CGS 15943). The promotion of forskolin-induced LTP provides a cellular basis behind caffeine's increase in capacity for sustained intellectual performance.

Adenosine↗
PubMed2003

Rapid mechano-sensory pathways code leg impact and elicit very rapid reflexes in insects.

The temporal sequence of mechanoreceptor input arriving at the motoneuron level in the central nervous system (CNS) after distal mechanical contact was studied for the locust middle leg. Different types of afferent information from potential contact areas after selective stimulation showed propagation times of no less than 8 ms from mechanosensory hairs, campaniform sensilla (CS) and spurs of the distal leg segments. Impact of the same mechanical stimuli, even if very delicate, elicits strain that is transferred in less than 1 ms via the cuticle and stimulates proximal CS on the trochanter and femur. These propagate the afferents that code distal leg contact in about 1 ms to the CNS, where they connect mono- and polysynaptically to motoneurons of the depressor trochanteris system. The elicited excitatory postsynaptic potentials (EPSPs) contribute to rapid efferent commands, since single EPSPs already rise near firing threshold of the motoneurons. The short delays in this mechano-neuronal-muscular pathway from the tip of a leg to the neuromuscular synapses (5-7 ms) can very rapidly raise muscle tension in the trochanteral depressors at new leg contacts during locust landing and locomotion. At substrate contact, proximal leg CS contribute to very rapid motor responses supporting the body.

Afferent Pathways↗
PubMed2004

Metabotropic glutamate receptor antagonist AIDA blocks induction of mossy fiber-CA3 LTP in vivo.

Metabotropic glutamate receptors (mGluR) are implicated in long-term memory storage. mGluR-I and mGluR-II antagonists impede various forms of learning and long-term potentiation (LTP) in animals. Despite the evidence linking mGluR to learning mechanisms, their role in mossy fiber-CA3 long-term potentiation (LTP) is not yet clear. To explain the involvement of mGluR-I in memory mechanisms, we examined the function of the mGluR-I antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA) on the induction of mossy fiber-CA3 LTP in vivo in male Sprague Dawley and Fischer 344 (F344) rats. Acute extracellular mossy fiber (MF) responses were evoked by stimulation of the MF bundle and recorded in the stratum lucidum of CA3. The excitatory postsynaptic potential (EPSP) magnitude was measured by using the initial slope of the field EPSP slope measured 2-3 ms after response onset. After collection of baseline MF-CA3 responses at 0.05 Hz, animals received either ((+/-))-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (N-methyl-D-aspartate-R antagonist, 10 mg/kg ip), naloxone (opioid-R antagonist, 10 mg/kg ip), or AIDA (mGluR antagonist, 1 mg/kg ip or 37.5 nmol ic). LTP was induced by two 100-Hz trains at the intensity sufficient to evoke 50% of the maximal response. Responses were collected for an additional 1 h. AIDA blocked induction of LTP in the mossy fiber pathway (P < 0.05) in both strains of rats after systemic and in Sprague Dawley rats after intrahippocampal injection.

Animals↗
PubMed1993

Monosynaptic GABA-mediated inhibitory postsynaptic potentials in CA1 pyramidal cells of hyperexcitable hippocampal slices from kainic acid-treated rats.

To examine the mechanisms underlying chronic epileptiform activity, field potentials were first recorded to identify hyperexcitable hippocampal slices from kainic acid-treated rats. Intracellular recordings were then obtained from CA1 pyramidal cells in the hyperexcitable areas. Twenty-two of the 47 cells responded to electrical stimulation of the stratum radiatum with a burst of two or more action potentials and reduced early inhibitory postsynaptic potentials, and were considered hyperexcitable. The remaining 25 cells were not hyperexcitable, displaying a single action potential and biphasic inhibitory postsynaptic potentials after stimulation, like control cells (n = 20). A long duration, voltage-sensitive component was associated with subthreshold excitatory postsynaptic potentials in the majority of hyperexcitable (12/15) and non-hyperexcitable (3/5) cells examined from kainic acid-treated animals, but not from cells (1/10) of control animals. Stimulation of stratum radiatum during pharmacological blockade of ionotropic excitatory amino acid synaptic transmission elicited biphasic monosynaptic inhibitory postsynaptic potentials in all hyperexcitable (n = 9) and non-hyperexcitable (n = 9) cells tested from kainate-treated animals, as well as in control cells (n = 8). The mean amplitude, latency to peak, equilibrium potential, and conductance changes of early and late monosynaptic inhibitory postsynaptic potentials were not different between cells of kainic acid-treated and control animals. In seven hyperexcitable cells tested, the early component of monosynaptic inhibitory postsynaptic potentials was significantly reduced by the GABAA receptor antagonist bicuculline (100-200 microM). The late component was significantly decreased by the GABAB receptor antagonist 2-hydroxysaclofen (1-2 mM; n = 3). Comparable effects were observed on early and late monosynaptic inhibitory postsynaptic potentials in non-hyperexcitable cells (n = 4) from kainic acid-treated animals and control cells (n = 5). These results suggest that GABAergic synapses on hyperexcitable hippocampal pyramidal cells of kainate-treated rats are intact and functional. Therefore, epileptiform activity in the kainate-lesioned hippocampus may not arise from a disconnection of GABAergic synapses made by inhibitory interneurons on pyramidal cells. The hyperexcitability may be due to underactivation of inhibitory interneurons and/or reorganization of excitatory inputs to pyramidal cells since, in kainate-treated animals, pyramidal cells appear to express additional excitatory mechanisms.

2-Amino-5-phosphonovalerate↗
PubMed2006

Nicotine-induced enhancement of synaptic plasticity at CA3-CA1 synapses requires GABAergic interneurons in adult anti-NGF mice.

The hippocampus, a key structure for learning and memory processes, receives an important cholinergic innervation and is densely packed with a variety of nicotinic acetylcholine receptors (nAChRs) localized on principal cells and interneurons. Activation of these receptors by nicotine or endogenously released acetylcholine enhances activity-dependent synaptic plasticity processes. Deficits in the cholinergic system produce impairment of cognitive functions that are particularly relevant during senescence and in age-related neurodegenerative pathologies. In particular, Alzheimer's disease (AD) is characterized by a selective loss of cholinergic neurons in the basal forebrain and nAChRs in particular regions controlling memory processes such as the cortex and the hippocampus. Field excitatory postsynaptic potentials were recorded in order to examine whether nicotine was able to regulate induction of long-term potentiation at CA3-CA1 synapses in hippocampal slices from adult anti-NGF transgenic mice (AD 11), a comprehensive animal model of AD, in which cholinergic deficits due to nerve growth factor depletion are accompanied by progressive Alzheimer-like neurodegeneration. Both AD 11 and wild-type (WT) mice exhibited short- and long-lasting synaptic plasticity processes that were boosted by nicotine. The effects of nicotine on WT and AD 11 mice were mediated by both alpha7- and beta2-containing nAChRs. In the presence of GABA(A) receptor antagonists, nicotine failed to boost synaptic plasticity in AD 11 but not in WT mice, indicating that in anti-NGF transgenic mice GABAergic interneurons are able to compensate for the deficit in cholinergic modulation of glutamatergic transmission. This compensation may occur at different levels and may involve the reorganization of the GABAergic circuit. However, patch-clamp whole-cell recordings from principal cells failed to reveal any change in spontaneous release of GABA following pressure application of nicotine to nearby GABAergic interneurons. Together, these experiments indicate that in AD 11 mice a rearrangement of the GABAergic circuit can 'rescue' nicotine-induced potentiation of synaptic plasticity. This may be relevant for developing proper therapeutic tools useful for the treatment of AD.

Alzheimer Disease↗
PubMed1997

Biological activities of N6,C8-disubstituted adenosine derivatives as partial agonists at rat brain adenosine A1 receptors.

C8-substituted derivatives of the adenosine A1 receptor-selective agonist N6-cyclopentyladenosine (CPA) were evaluated as potential partial adenosine A1 receptor agonists in rat brain. Potencies and efficacies of 8-alkylamino-CPA derivatives were determined in G protein activation assays by their ability to stimulate binding of [35S]guanosine-5'-(gamma-thio)triphosphate ([35S]GTPgammaS) to rat forebrain membranes, by their ability to inhibit forskolin-stimulated adenylate cyclase, and by inhibition of evoked field excitatory postsynaptic potentials (field EPSPs) in hippocampal slices. EC50 values around 1 microM were determined for all C8-substituted CPA derivatives. Increase in chain length of the substituent gradually reduced agonist efficacy in [35S]GTPgammaS binding studies. Only C8-methylamino-, C8-ethylamino- and C8-propylamino-CPA inhibited forskolin-stimulated adenylate cyclase. In contrast, 8-methylamino- and 8-butylamino-CPA were the compounds of highest intrinsic activity in inhibition of field EPSPs in the hippocampus, followed by 8-ethylamino-CPA. 8-Cyclopentylamino-CPA was without effect in this tissue, and the propylamino derivative, when applied cumulatively, caused an inhibition which was smaller the higher the concentration used and the longer the application, which is suggestive of drug-induced desensitization. These data indicate that 8-aminoalkyl-substituted CPA derivatives act as partial agonists on the brain and may serve as valuable tools to dissect adenosine A1 receptor mediated signal trafficking in various organs.

Adenosine↗
PubMed2000

The anticonvulsant remacemide and its metabolite AR-R12495AA attenuate spinal synaptic transmission and carrageenan-induced inflammation in the young rat.

The effects of the anticonvulsants remacemide [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride] and its des -glycinated metabolite AR-R12495AA [(+/-)-1-methyl-1,2-diphenylethylamine- monohydrochloride] on primary afferent-induced synaptic transmission and frequency-dependent summation of synaptic potentials were assessed in the young rat spinal cord in vitro. Behavioural studies in the rat determined the effects of these anticonvulsant compounds in the carrageenan model of inflammation. Recordings of the extracellular dorsal root-evoked ventral root potential (DR-VRP) revealed a significant reduction of the duration and t(1)-(2)decay of the long latency, slow DR-VRP by remacemide (50 and 100 microM) and AR-R12495AA (25, 50 and 100 mM). The short-latency, fast monosynaptic DR-VRP peak was reduced by only the highest concentration of AR-R12495AA (100 microM). In intracellular dorsal root-evoked excitatory postsynaptic potentials (DR-EPSPs) of single ventral horn neurons, AR-R12495AA (100 microM) attenuated the time course of the long-latency (slow) EPSP. Frequency-dependent (0.5-2.0 Hz) summation of dorsal root-evoked synaptic events (recorded extracellularly as the cumulative ventral root depolarization (CVRD), and intracellularly as wind-up) was attenuated by remacemide (100 microM) and AR-R12495AA (50 and 100 microM). Pre-treatment with intra-peritoneal injection of 75 mg/kg of remacemide or AR-R12495AA caused a significant reduction of carrageenan-induced mechanical hyperalgesia and oedema. These electrophysiological and behavioural data provide evidence that remacemide and AR-R12495AA may also possess analgesic and anti-inflammatory activity.

Acetamides↗
PubMed1998

Interaction of GABAB-mediated inhibition with voltage-gated currents of pyramidal cells: computational mechanism of a sensory searchlight.

Interaction of GABAB-mediated inhibition with voltage-gated currents of pyramidal cells: computational mechanism of a sensory searchlight. J. Neurophysiol. 80: 3197-3213, 1998. This study examines, in the in vitro electrosensory lateral line lobe (ELL) slice preparation, mono- and disynaptic inhibition in pyramidal cells evoked by stimulation of the direct descending pathway from nucleus praeminentialis (Pd). The pathway forms the stratum fibrosum (StF) in the ELL and consists of excitatory fibers from Pd stellate cells that make monosynaptic contact with pyramidal cells and disynaptic inhibitory contacts via local interneurons and of GABAergic inhibitory fibers from Pd bipolar cells. Single or tetanic stimulation (physiological rates of 100-200 Hz) of the StF produced excitatory postsynaptic potentials (EPSPs) or compound EPSPs in ELL pyramidal cells. Slow (>600 ms) and fast inhibitory postsynaptic potentials (IPSPs; 5-50 ms) also were evoked. Application of gamma-aminobutyric acid-A (GABAA) antagonists blocked the fast inhibition and dramatically increased the firing rate response to StF tetanic stimuli. GABAA antagonists also increased the amplitude of the slow IPSP. The slow IPSP was reduced by GABAB antagonists. Blockade of excitatory amino acid (EAA) synaptic transmission allowed the monosynaptic bipolar-cell-mediated inhibition to be studied in isolation: EAA antagonists blocked most of the EPSP response to StF stimulation leaving fast and (an increased amplitude) slow IPSP components. The bipolar-cell IPSPs were mediated by GABAA and GABAB receptors as they were sensitive to GABAA and GABAB antagonists. The bipolar-cell IPSPs scaled with stimulation rate (20-400 Hz), reaching a maximum amplitude at 200 Hz. Inhibitory efficacy of bipolar-cell slow IPSPs were tested by their ability to reduce spiking in the face of sustained or brief current pulses. Established spike trains (by sustained injected current) were little affected by the onset of the slow IPSP. Weak brief currents injected during the slow IPSP were strongly inhibited. Strong brief currents could overcome the slow IPSP inhibitory effect. Inhibition was observed to interact with the intrinsic IA-like K+ currents to produce a complex control of cell spiking. Hyperpolarizing inhibition removes inactivation of IA to prevent subsequent inputs from driving the cell to threshold. Established depolarizing inputs, having allowed IA to inactivate, enable the cell to be highly sensitive to further depolarizing input. The term "conditional inhibition" is proposed to describe the general phenomenon where synaptic inhibition interacts with voltage-sensitive intrinsic currents.

Animals↗
PubMed2002

Disturbance of hippocampal long-term potentiation after transient ischemia in GFAP deficient mice.

GFAP (glial fibrillary acidic protein) is an intermediate filament protein found exclusively in the astrocytes of the central nervous system. We studied the role of GFAP in the neuronal degeneration in the hippocampus after transient ischemia using knockout mice. Wild-type C57 Black/6 (GFAP(+/+)) mice and mutant (GFAP(-/-)) mice were subjected to occlusion of both carotid arteries for 5-15 min. Hippocampal slices were prepared 3 days after reperfusion and the field excitatory postsynaptic potentials (fEPSP) in the CA1 were recorded. High frequency stimulation induced robust long-term potentiation (LTP) in GFAP(-/-), as in GFAP(+/+) mice. After ischemia, however, the LTP in GFAP(-/-) was significantly depressed. Similarly, paired pulse facilitation (PPF) displayed little difference between GFAP(+/+) and GFAP(-/-), but after ischemia, the PPF in GFAP(-/-) showed a depression. Histological study revealed that loss of CA1 and CA3 pyramidal neurons after ischemia was marked in GFAP(-/-). MAP2 (dendritic) immunostaining in the post-ischemic hippocampus showed little difference but NF200 (axonal) immunoreactivity was reduced in GFAP(-/-). S100beta (glial) immunoreactivity was similar in the post-ischemic hippocampus of the GFAP(+/+) and GFAP(-/-), indicating that reactive astrocytosis did not require GFAP. Our results suggest that GFAP has an important role in astrocyte-neural interactions and that ischemic insult impairs LTP and accelerates neuronal death.

Animals↗
PubMed1999

Interaction of the structurally related aconitum alkaloids, aconitine and 6-benzyolheteratisine, in the rat hippocampus.

Aconitine is a highly toxic diterpenoid alkaloid occurring in plants of the Aconitum genus. Aconitine is known to shift the voltage-dependence of the voltage-dependent Na(+) channel towards hyperpolarized direction, thereby leading to a permanent activation of the channel. 6-benzoylheteratisine is a plant alkaloid which is structurally related with aconitine. The aim of the present study was to investigate the interaction of aconitine and 6-benzoylheteratisine in the rat hippocampus. The experiments were carried out as extracellular recordings of stimulus evoked population spikes and field excitatory postsynaptic potential (EPSP) in rat hippocampal slices. Aconitine (10-100 nM) exerted a concentration-dependent decrease in the amplitude of the orthodromic population spike. When aconitine was applied in presence of 6-benzoylheteratisine (3 microM), the concentration-response curve was shifted to the right. Furthermore, the complete suppression of the population spike evoked by 100 nM aconitine was reversed by 10 microM 6-benzoylheteratisine. The closely related alkaloid heteratisine (3 and 30 microM), however, was not capable to antagonize the aconitine action. 6-benzoylheteratisine shifted the input-output relationship of the presynaptic fiber spike as function of the stimulation intensity and the input-output relationship of the field EPSP as function of the presynaptic fiber spike to the right. Thus, electrophysiologically this alkaloid seems to inhibit predominantly the excitability of the afferent fibres and, in consequence, neurotransmission between Schaffer collaterals and the CA1 neurons, thereby suppressing the firing of the latter. Spontaneously occurring epileptiform activity in area CA3 elicited by omission of Mg(2+) and elevation of K(+) was attenuated by 6-benzoylheteratisine (1 and 10 microM). Patch clamp studies performed on cultured rat hippocampal pyramidal cells revealed an inhibitory action of 6-benzoylheteratisine on whole cell Na(+) currents. It is concluded that the inhibitory and antiepileptiform effect of ajacine and lappaconitine is mediated by an inhibition of the voltage-dependent Na(+) channel which might be important for filtering high frequency bursts of action potentials characteristic for epileptiform activity in the hippocampus. Thus, 6-benzoylheteratisine seems to be a naturally occurring antagonist of the Na(+) channel activator aconitine.

Aconitine↗
PubMed1999

Enhanced synaptic transmission and reduced threshold for LTP induction in fyn-transgenic mice.

To elucidate the physiological role of Fyn, we analysed the properties of synaptic transmission and synaptic plasticity in hippocampal slices of mice overexpressing either wild-type Fyn (w-Fyn) or its constitutively active mutant (m-Fyn). These fyn-transgenes were driven by the calcium/calmodulin-dependent protein kinase II alpha promoter which turned on in the forebrain neurons including hippocampal pyramidal cells and in late neural development. In the hippocampal slices expressing m-Fyn the paired-pulse facilitation was reduced and the basal synaptic transmission was enhanced. A weak theta-burst stimulation, which was subthreshold for the induction of long-term potentiation (LTP) in control slices, elicited LTP in CA1 region of the slices expressing m-Fyn. When a relatively strong stimulation was applied, the magnitude of LTP in m-Fyn slices was similar to that in control slices. By contrast, the basal synaptic transmission and the threshold for the induction of LTP were not altered in the slices overexpressing wild-type Fyn. To examine the effect of expression of m-Fyn on GABAergic inhibitory system, we applied bicuculline, a GABAA receptor blocker, to the hippocampal slices. The ability of bicuculline to enhance excitatory postsynaptic potentials was attenuated in slices expressing m-Fyn, suggesting that the overexpression of m-Fyn reduced the GABAergic inhibition. The enhancement of synaptic transmission and the reduction of GABAergic inhibition may contribute to the enhanced seizure susceptibility in the mice expressing m-Fyn. Thus, these results suggest that regulation of Fyn tyrosine kinase activity is important for both synaptic transmission and plasticity.

Animals↗
PubMed1998

Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1.

Long-term potentiation (LTP) of the Schaffer collateral/commissural inputs to CA1 in the hippocampus was shown to consist of N-methyl-D-aspartate receptor (NMDAR) and voltage-dependent calcium channel (VDCC) dependent forms. In this study, the relative contributions of these two forms of LTP in in vitro hippocampal slices from young (2 mo) and old (24 mo) Fischer 344 rats were examined. Excitatory postsynaptic potentials (EPSP) were recorded extracellularly from stratum radiatum before and after a tetanic stimulus consisting of four 200-Hz, 0.5-s trains given 5 s apart. Under control conditions, a compound LTP consisting of both forms was induced and was similar, in both time course and magnitude, in young and old animals. NMDAR-dependent LTP (nmdaLTP), isolated by the application of 10 microM nifedipine (a voltage-dependent calcium channel blocker), was significantly reduced in magnitude in aged animals. The VDCC dependent form (vdccLTP), isolated by the application of 50 microM D,L-2-amino-5-phosphonvalerate (APV), was significantly larger in aged animals. Although both LTP forms reached stable values 40-60 min posttetanus in young animals, in aged animals vdccLTP increased and nmdaLTP decreased during this time. In both young and old animals, the sum of the two isolated LTP forms approximated the magnitude of the compound LTP, and application of APV and nifedipine or genestein (a tyrosine kinase inhibitor) together blocked potentiation. These results suggest that aging causes a shift in synaptic plasticity from NMDAR-dependent mechanisms to VDCC-dependent mechanisms. The data are consistent with previous findings of increased L-type calcium current and decreased NMDAR number in aged CA1 cells and may help explain age-related deficits in learning and memory.

2-Amino-5-phosphonovalerate↗
PubMed1999

Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release.

Previously, serotonin (5-HT) was found to induce a marked increase in glutamatergic spontaneous excitatory postsynaptic currents (EPSCs) in apical dendrites of layer V pyramidal cells of prefrontal cortex; this effect was mediated by 5-HT2A receptors, a proposed site of action of hallucinogenic and atypical antipsychotic drugs. Unexpectedly, although the effect of 5-HT was Ca2+-dependent and tetrodotoxin-sensitive, it did not appear to involve the activation of excitatory afferent impulse flow. This paradox prompted us to investigate (in rat brain slices) whether 5-HT was acting through an atypical mode of excitatory transmitter release. We found that the frequency of 5-HT-induced spontaneous EPSCs was fully supported by Sr2+ in the absence of added Ca2+, implicating the mechanism of asynchronous transmitter release which has been linked to the high-affinity Ca2+-sensor synaptotagmin III. Although the early, synchronous component of electrically evoked EPSCs was reduced while 5-HT was being applied, late, nonsynchronous components were enhanced during 5-HT washout and also by the 5-HT2 partial agonist 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI); the effect of DOI was blocked by a selective 5-HT2A antagonist (MDL 100,907). This late, nonsynchronous component was distinct from conventional polysynaptic EPSCs evoked in the presence of the GABAA antagonist bicuculline, but resembled asynchronous glutamatergic excitatory postsynaptic potentials (EPSPs) evoked in the presence of Sr2+. An enhancement of asynchronous EPSCs by a specific neurotransmitter receptor has not been reported previously. The possible role of excessive asynchronous transmission in the cerebral cortex in mediating the hallucinogenic effects of 5-HT2A agonists such as DOI is discussed.

Animals↗
PubMed2001

Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation.

Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in gamma-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance.

Animals↗
PubMed1998

Control of recurrent inhibition of the lateral posterior-pulvinar complex by afferents from the deep layers of the superior colliculus of the rabbit.

We investigated the effect of stimulation of the deep layers of the superior colliculus (SC) on the recurrent inhibition of the lateral posterior-pulvinar complex (LP) in anesthetized rabbits. Intracellular recordings from 23 relay cells in LP showed that they responded to SC stimulation with a long-lasting (140.2 +/- 19.6 ms; mean +/- SD) inhibitory postsynaptic potential (IPSP), which sometimes was followed by a rebound burst of spikes. The same SC stimulation evoked a burst of spikes in extracellular recordings from 31 recurrent inhibitory interneurons in the LP-cortical pathway, which were located in the ventral part of the visual sector of the thalamic reticular nucleus. The mean latency of the burst in reticular cells was 1.6 ms shorter than that of the IPSP in LP relay cells, suggesting that the IPSP in LP cells was mediated by these reticular cells. Intracellular recordings from nine reticular cells showed that the burst of spikes evoked by SC stimulation resulted from an excitatory postsynaptic potential that was always followed by a long-lasting (143.3 +/- 24.0 ms) IPSP. Stimulation of the contralateral predorsal bundle, the main output pathway of deep SC neurons, elicited similar responses in LP cells or reticular neurons with latencies longer than those from SC stimulation. The latency difference between the responses to predorsal bundle and SC stimulation is equal to the antidromic conduction time of predorsal bundle fibers, suggesting that the inhibition in LP originates from the activation of predorsal bundle-projecting neurons. The response characteristics of the inhibitory circuit of LP and of the lateral geniculate nucleus to SC stimulation are strikingly similar, implying that a similar circuit is used by predorsal bundle-projecting neurons to control the recurrent inhibition in both lateral geniculate nucleus and LP. Because the predorsal bundle-projecting neurons are believed to be involved in the initiation of saccadic eye movements, we suggest that the inhibitory circuits may play an important role in modulating ascending visual information during saccadic eye movements.

Animals↗
PubMed2000

Multiple mechanisms of fast excitatory synaptic transmission in the enteric nervous system.

The enteric nervous system (ENS) can control gastrointestinal function independent of direct connections with the central nervous system. Enteric nerves perform this important function using multiple mechanisms of excitatory neurotransmission in enteric ganglia. Fast excitatory synaptic transmission in the autonomic nervous system (ANS) is largely mediated by acetylcholine (ACh) acting at nicotinic cholinergic receptors but in the ENS there are noncholinergic fast excitatory neurotransmitters. There are two broad types of neurons in the ENS: S neurons and AH neurons. S neurons are interneurons and motoneurons while AH neurons are sensory neurons. Three subsets of S neurons in the myenteric plexus can be distinguished on the basis of the neurotransmitters producing fast excitatory postsynaptic potentials (fEPSPs) in each subset. In one subset, fEPSPs are mediated solely by ACh acting at nicotinic cholinergic receptors. In a second subset of S neurons, ATP acting at P2X purine receptors and ACh contribute to the fEPSP while in a third subset, fEPSPs are mediated by 5-hydroxytryptamine (5-HT) acting at 5-HT(3) receptors and ACh. Some AH neurons also receive fast excitatory synaptic input. The fEPSPs recorded from AH neurons are mediated ACh and also by glutamate acting at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Multiple mechanisms of fast excitatory synaptic transmission in the ENS are likely to contribute to its capacity to regulate complex gastrointestinal functions.

Animals↗
PubMed1998

Sensitivity of H-reflexes and stretch reflexes to presynaptic inhibition in humans.

The sensitivity of soleus H-reflexes, T-reflexes, and short-latency stretch reflexes (M1) to presynaptic inhibition evoked by a weak tap applied to the biceps femoris tendon or stimulation of the common peroneal nerve (CPN) was compared in 17 healthy human subjects. The H-reflex was strongly depressed for a period lasting up to 300-400 ms (depression to 48 +/- 23%, mean +/- SD, of control at a conditioning test interval of 70 ms) by the biceps femoris tendon tap. In contrast, the short-latency soleus stretch reflex elicited by a quick passive dorsiflexion of the ankle joint was not depressed. The soleus T-reflex elicited by an Achilles tendon tap was only weakly depressed (92 +/- 8%). The H-reflex was also significantly more depressed than the T-reflex at long intervals (>15 ms) after stimulation of CPN (H-reflex 63 +/- 14%, T-reflex 91 +/- 13%; P < 0. 01). However, the short-latency (2 ms) disynaptic reciprocal Ia inhibition evoked by stimulation of CPN was equally strong for H- and T-reflexes (H-reflex 72 +/- 10%, T-reflex 67 +/- 13%; P = 0.07). Peaks in the poststimulus time histogram (PSTH) of the discharge probability of single soleus motor units (n = 53) elicited by an Achilles tendon tap had a longer duration than peaks evoked by electrical stimulation of the tibial nerve (on average 5.0 ms as compared with 2.7 ms). All parts of the electrically evoked peaks were depressed by the conditioning biceps femoris tendon tap (average depression to 55 +/- 27% of control; P < 0.001). A similar depression was observed for the initial 2 ms of the peaks evoked by the Achilles tendon tap (69 +/- 48%; P < 0.001), but the last 2 ms were not depressed. Conditioning stimulation of the CPN at long intervals (>15 ms) also depressed all parts of the electrically evoked PSTH peaks (n = 34; average 65%; P < 0.001) but had only a significant effect on the initial 2 ms of the peaks evoked by the Achilles tendon tap (85%; P < 0.001). We suggest that the different sensitivity of mechanically and electrically evoked reflexes to presynaptic inhibition is caused by a difference in the shape and composition of the excitatory postsynaptic potentials underlying the two reflexes. This difference may be explained by a different composition and/or temporal dispersion of the afferent volleys evoked by electrical and mechanical stimuli. We conclude that it is not straightforward to predict the modulation of stretch reflexes based on observations of H-reflex modulation.

Adult↗
PubMed2002

Differential effects of repeated imipramine on hippocampal responsiveness to adenosine and serotonin.

Imipramine-induced enhancement of the inhibitory action of 5-HT(lA) receptor activation in hippocampal pyramidal neurons has been attributed to alterations in the transduction mechanism that involves G protein-dependent opening of K(+) channels. Postsynaptic 5-HT(lA) and adenosine Al receptors may share that transduction pathway. We investigated the influence of repeated imipramine administration on 5-HT(lA) and adenosine A1 receptor-mediated effects in rat hippocampal slices. Repeated imipramine selectively enhanced the postsynaptic effects of 5-HT(1A) receptor activation, including hyperpolarization and reduction of input resistance of neurons and reduction of the population spike amplitude. In contrast, after imipramine treatment only the presynaptic effect of adenosine receptor agonists, a decrease of the field excitatory postsynaptic potential, was enhanced. The data demonstrate that alterations in the presumed common transduction mechanism that was postulated for the 5-HT(lA) and adenosine A1 receptor-mediated activation of K(+) channels are not involved in the effect of repeated imipramine administration.

8-Hydroxy-2-(di-n-propylamino)tetralin↗