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PubMed1998

Synaptic interactions between smooth and spiny neurones in layer 4 of cat visual cortex in vitro.

1. Dual intracellular recording was used to examine the interactions between neighbouring spiny (excitatory) and smooth (inhibitory) neurones in layer 4 of cat visual cortex in vitro. Synaptic connections were found in seventeen excitatory-inhibitory neurone pairs, along with one inhibitory-inhibitory connection. 2. Fast excitatory inputs onto smooth neurones (basket cells) from spiny cells (spiny stellate or pyramidal cells) (n = 6) produce large excitatory postsynaptic potentials (EPSPs) of up to 4 mV mean amplitude, whereas basket cells evoke slower inhibitory postsynaptic potentials (IPSPs) in their postsynaptic targets (n = 17), of smaller amplitude (up to 1.6 mV at membrane potentials of -60 mV). 3. Both types of PSP appear to be multiquantal, and both may exhibit depression of up to 60 % during short trains of presynaptic spikes. This depression can involve presynaptic and/or postsynaptic factors. 4. One-third (n = 5) of the spiny cell-smooth cell pairs tested were reciprocally connected, and in the one pair for which the suprathreshold interactions were comprehensively investigated, the pattern of basket cell firing was strongly influenced by the activity in the connected excitatory neurone. The basket cell was only effective in inhibiting spiny cell firing when the excitatory neurone was weakly driven.

Animals↗
PubMed2003

Inhibitory control of rat lateral amygdaloid projection cells.

The amygdaloid complex has long been implicated in seizure disorders. Yet, projection cells of the lateral amygdaloid nucleus (LA) display little spontaneous activity suggesting that this seizure prone structure is normally controlled by strong inhibitory mechanisms. This control is achieved in part by local interneurons; however, a synaptically activated, Ca(2+)-dependent K(+) (K(Ca)) conductance has recently been identified as a second major inhibitory mechanism. In the present study, we investigated which K(Ca) channels underlie this conductance, and their roles in the generation of the synaptic responses and spike adaptation of LA projection cells. Intracellular recordings were obtained from LA projection cells in barbiturate-anesthetized rats. In recordings with K-acetate pipettes, perirhinal stimulation evoked an initial excitatory postsynaptic potential (EPSP) followed by a prolonged monophasic hyperpolarization, similar to what was observed in cats under in vivo conditions, and distinct from the multiphasic hyperpolarization observed previously in rodents with in vitro recordings. This indicates that differences in the cellular environment, not interspecies differences, are responsible for the differing response profiles previously reported. In recordings with pipettes containing 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid or Cs-acetate the reversal potentials were significantly more positive than those recorded with K-acetate, consistent with a K(Ca) conductance contribution to the response. To investigate the K(Ca) channels underlying this conductance, intracellular recordings were obtained while perfusing the LA with Ringer's solution and then switching to a solution containing charybdotoxin, isoproterenol, or apamin. Charybdotoxin and isoproterenol produced positive shifts in the reversal potential, whereas apamin did not. By contrast, all three substances decreased adaptation during spike trains elicited by depolarizing current injections. These results suggest that intermediate (IK) and small (SK) conductance K(Ca) channels limit LA projection cell excitability, with IK channels involved in controlling both the synaptic response and intrinsic excitability of these neurons, and SK channels being involved only in the latter.

Amygdala↗
PubMed2000

Direct measurement of adenosine release during hypoxia in the CA1 region of the rat hippocampal slice.

We have used an enzyme-based, twin-barrelled sensor to measure adenosine release during hypoxia in the CA1 region of rat hippocampal slices in conjunction with simultaneous extracellular field recordings of excitatory synaptic transmission. When loaded with a combination of adenosine deaminase, nucleoside phosphorylase and xanthine oxidase, the sensor responded linearly to exogenous adenosine over the concentration range 10 nM to 20 microM. Without enzymes, the sensor when placed on the surface of hippocampal slices recorded a very small net signal during hypoxia of 40 +/- 43 pA (mean +/- s.e.m.; n = 7). Only when one barrel was loaded with the complete sequence of enzymes and the other with the last two in the cascade did the sensor record a large net difference signal during hypoxia (1226 +/- 423 pA; n = 7). This signal increased progressively during the hypoxic episode, scaled with the hypoxic depression of the simultaneously recorded field excitatory postsynaptic potential and was greatly reduced (67 +/- 6.5 %; n = 9) by coformycin (0.5-2 microM), a selective inhibitor of adenosine deaminase, the first enzyme in the enzymic cascade within the sensor. For 5 min hypoxic episodes, the sensor recorded a peak concentration of adenosine of 5.6 +/- 1.2 microM (n = 16) with an IC(50) for the depression of transmission of approximately 3 microM. In slices pre-incubated for 3-6 h in nominally Ca(2+)-free artificial cerebrospinal fluid, 5 min of hypoxia resulted in an approximately 9-fold greater release of adenosine (48.9 +/- 17.7 microM; n = 6). High extracellular Ca(2+) (4 mM) both reduced the adenosine signal recorded by the sensor during hypoxia (3.5 +/- 0.6 microM; n = 4) and delayed the hypoxic depression of excitatory synaptic transmission.

Adenosine↗
PubMed1997

Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex.

Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex. J. Neurophysiol. 78: 2546-2559, 1997. Physiological analysis in the companion paper demonstrated that gamma-aminobutyric acid-A (GABAA)-mediated inhibition in piriform cortex is generated by circuits that are largely independent in apical dendritic and somatic regions of pyramidal cells and that GABAA-mediated inhibitory postsynaptic currents (IPSCs) in distal dendrites have a slower time course than those in the somatic region. This study used modeling methods to explore these characteristics of GABAA-mediated inhibition with respect to regulation of the N-methyl--aspartate (NMDA) component of excitatory postsynaptic potentials. Such regulation is relevant to understanding NMDA-dependent long-term potentiation (LTP) and the integration of repetitive synaptic inputs that can activate the NMDA component as well as pathological processes that can be activated by overexpression of the NMDA component. A working hypothesis was that the independence and differing properties of IPSCs in apical dendritic and somatic regions provide a means whereby the NMDA component and other dendritic processes can be controlled by way of GABAergic tone without substantially altering system excitability. The analysis was performed on a branched compartmental model of a pyramidal cell in piriform cortex constructed with physiological and anatomic data derived by whole cell patch recording. Simulations with the model revealed that NMDA expression is more effectively blocked by the slow GABAA component than the fast. Because the slow component is present in greater proportion in apical dendritic than somatic regions, this characteristic would increase the capacity of dendritic IPSCs to regulate NMDA-mediated processes. The simulations further revealed that somatic-region GABAergic inhibition can regulate the generation of action potentials with little effect on the NMDA component generated by afferent fibers in apical dendrites. As a result, if expression of the NMDA component or other dendritic processes were enabled by selective block of dendritic inhibition, for example, by centrifugal fiber systems that may regulate learning and memory, the somatic-region IPSC could preserve system stability through feedback regulation of firing without counteracting the effect of the dendritic-region block. Simulations with paired inputs revealed that the dendritic GABAA-mediated IPSC can regulate the extent to which a strong excitatory input facilitates the NMDA component of a concurrent weak input, providing a possible mechanism for control of "associative LTP" that has been demonstrated in this system. Postsynaptic GABAB-mediated inhibition had less effect on the NMDA component than either the fast or slow GABAA components. Depolarization from a concomitant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component also was found to have comparatively little effect on current through the NMDA channel because of its brief time course.

2-Amino-5-phosphonovalerate↗
PubMed2000

Identified motor terminals in Drosophila larvae show distinct differences in morphology and physiology.

In Drosophila, the type I motor terminals innervating the larval ventral longitudinal muscle fibers 6 and 7 have been the most popular preparation for combining synaptic studies with genetics. We have further characterized the normal morphological and physiological properties of these motor terminals and the influence of muscle size on terminal morphology. Using dye-injection and physiological techniques, we show that the two axons supplying these terminals have different innervation patterns: axon 1 innervates only muscle fibers 6 and 7, whereas axon 2 innervates all of the ventral longitudinal muscle fibers. This difference in innervation pattern allows the two axons to be reliably identified. The terminals formed by axons 1 and 2 on muscle fibers 6 and 7 have the same number of branches; however, axon 2 terminals are approximately 30% longer than axon 1 terminals, resulting in a corresponding greater number of boutons for axon 2. The axon 1 boutons are approximately 30% wider than the axon 2 boutons. The excitatory postsynaptic potential (EPSP) produced by axon 1 is generally smaller than that produced by axon 2, although the size distributions show considerable overlap. Consistent with vertebrate studies, there is a correlation between muscle fiber size and terminal size. For a single axon, terminal area and length, the number of terminal branches, and the number of boutons are all correlated with muscle fiber size, but bouton size is not. During prolonged repetitive stimulation, axon 2 motor terminals show synaptic depression, whereas axon 1 EPSPs facilitate. The response to repetitive stimulation appears to be similar at all motor terminals of an axon.

Animals↗
PubMed2001

Opposing actions of nitric oxide on synaptic inputs of identified interneurones in the central nervous system of the crayfish.

Little is known of the action of nitric oxide (NO) at the synaptic level on identified interneurones in local circuits that process mechanosensory signals. Here, we examine the action of NO in the terminal abdominal ganglion of the crayfish Pacifastacus leniusculus, where it has modulatory effects on the synaptic inputs of 17 identified ascending interneurones mediated by electrical stimulation of a sensory nerve. To analyse the role of NO in the processing of sensory signals, we bath-applied the NO donor SNAP, the NO scavenger PTIO, the nitric oxide synthase (NOS) inhibitor l-NAME, the NOS substrate l-arginine, a cyclic GMP (cGMP) analogue, 8-Br-cGMP, and the soluble guanylate cyclase (sGC) inhibitor ODQ. The effects of these chemicals on the synaptic inputs of the interneurones could be divided into two distinct classes. The NO donor SNAP enhanced the inputs to one class of interneurone (class 1) and depressed those to another (class 2). Neither the inactive isomer NAP nor degassed SNAP had any effect on the inputs to these same classes of interneurone. The NO scavenger PTIO caused the opposite effects to those of the NO donor SNAP, indicating that endogenous NO may have an action in local circuits. Preventing the synthesis of NO using l-NAME had the opposite effect to that of SNAP on each response class of interneurone. Increasing the synthesis of endogenous NO by applying l-arginine led to effects on both response classes of interneurone similar to those of SNAP. Taken together, these results suggested that NO was the active component in mediating the changes in amplitude of the excitatory postsynaptic potentials. Finally, the effects of 8-Br-cGMP were similar to those of the NO donor, indicating the possible involvement of a NO-sensitive guanylate cyclase. This was confirmed by preventing the synthesis of cGMP by sGC using ODQ, which caused the opposite effects to those of 8-Br-cGMP on the two response classes of interneurone. The results indicate that a NO--cGMP signal transduction pathway, in which NO regulates transmitter release from mechanosensory afferents onto intersegmental ascending interneurones, is probably present in the local circuits of the crayfish.

Animals↗
PubMed1998

Facilitating pyramid to horizontal oriens-alveus interneurone inputs: dual intracellular recordings in slices of rat hippocampus.

1. In adult rat hippocampal slices, simultaneous intracellular recordings from pyramidal cells in CA1 and interneurones near the stratum oriens-alveus border revealed excitatory connections that displayed facilitation on repetitive activation in twelve of thirty-six pairs tested. 2. Postsynaptic interneurones were classified as horizontal oriens-alveus interneurones by the pronounced 'sag' in response to hyperpolarizing current injection, high levels of spontaneous synaptic activity and by the morphology of their somata and dendrites, which were confined to stratum oriens-alveus and their axons which projected to stratum lacunosum-moleculare where they ramified extensively, in the region of entorhinal cortex input to CA1. 3. Excitatory postsynaptic potentials (EPSPs) elicited by single pyramidal cells were 0 to 12 mV in amplitude. Mean EPSP amplitude (single spikes) was 0.93 +/- 1. 06 mV at -70 +/- 2.3 mV (n = 10). The rise time was 1.2 +/- 0.5 ms and the width at half-amplitude was 7.5 +/- 4.7 ms. 4. EPSPs fluctuated greatly in amplitude; the mean coefficient of variation was 0.84 +/- 0.37 for the first EPSP and 0.47 +/- 0.24 for the second. Apparent failures of transmission frequently occurred after first presynaptic spikes but less frequently after the second or subsequent spikes in brief trains. 5. EPSPs displayed facilitation at membrane potentials between -80 mV and spike threshold. Second EPSPs within 20 ms of the first were 253 +/- 48 % (range, 152-324 %) of the mean first EPSP amplitude. Third EPSPs within 60 ms were 266 +/- 70 % (range, 169-389 %) and fourth EPSPs within 60-120 ms were 288 +/- 71 % (range, 188-393 %). Both proportions of apparent failures of transmission and coefficient of variation analysis indicated a presynaptic locus for this facilitation.

Animals↗
PubMed2006

De Novo synthesis of CREB in a presynaptic neuron is required for synaptic enhancement involved in memory consolidation.

Interaction between the activator type of cyclic AMP response element binding protein (CREB1) and the repressor type (CREB2) results in determining the emergence of long-lasting synaptic enhancement involved in memory consolidation. However, we still do not know whether the constitutively expressed forms of CREB are enough or the newly synthesized forms are required for the synaptic enhancement. In addition, if the newly synthesized forms are needed, we must determine the time for translation of CREB from its mRNA. We applied the methods of RNA interference and real-time polymerase chain reaction (PCR) to CREB in the cerebral giant cells of Lymnaea. The cerebral giant cells play an important role in associative learning and employ a CREB cascade for the synaptic enhancement to neurons such as the B1 motoneurons. We injected the small interfering RNA (siRNA) of CREB1 or CREB2 into the cerebral giant cells and examined the changes in amplitude of excitatory postsynaptic potential (EPSP) recorded in the B1 motoneurons. The changes in the amounts of CREB1 and CREB2 mRNAs were also examined in the cerebral giant cells. The EPSP amplitude was suppressed 15 min after injection of CREB1 siRNA, whereas that was augmented 60 min after injection of CREB2 siRNA. In the latter case, the decrease in the amount of CREB2 mRNA was confirmed by real-time PCR. Our results showed that the de novo synthesized forms of CREB are required within tens of minutes for the synaptic enhancement in memory consolidation.

Animals↗
PubMed1998

Transplanted embryonic entorhinal neurons make functional synapses in adult host hippocampus.

Grafts of embryonic entorhinal cortex (EC) or non-entorhinal cortex (NEC) were placed into the hippocampus of adult rats with transection of the perforant paths. Graft-host connectivity was investigated at 4-6 months post-transplantation by recording extracellular evoked responses in hippocampal slice preparations. Electrical stimulation of the grafts evoked excitatory postsynaptic potentials (EPSPs) in the outer molecular layer of the dentate gyrus, and the stratum lacunosum moleculare of CA1, CA3, and elicited population spikes in the granule cell layer and the pyramidal cell layer of CA1, but not CA3. While the latencies and the forms of these evoked response were similar to those in matched control slices from the normal animals, the amplitudes were smaller than normal controls. However, in the slices with NEC grafts, no such responses were recorded when stimulus was applied in similar position in the grafts. The findings suggest that grafted entorhinal neurons make viable synaptic connections with the host hippocampus.

Animals↗
PubMed2006

Nitric oxide mediates interactions between GABAA receptors and adenosine A1 receptors in the rat hippocampus.

Adenosine and gamma-aminobutyric acid (GABA) are both major inhibitory neuromodulators/neurotransmitters in the CNS. We now investigated if endogenous GABA modulates adenosine A(1)-mediated action on synaptic transmission in the hippocampus. Field excitatory postsynaptic potentials (fEPSP) were recorded from the CA(1) area of rat hippocampal slices. The adenosine analogue 2-chloroadenosine (0.15-1 microM) inhibited synaptic transmission with an EC(50) of 398 nM. Blocking GABA(A) receptors with the specific antagonists, bicuculline (10 microM) or picrotoxin (10 microM) potentiated the inhibitory effect of 2-chloroadenosine. The concentration-response curve for 2-chloroadenosine was displaced to the left by a factor of 2 (EC(50)=210 nM) in the presence of bicuculline (10 microM). GABA(A) receptor blockade also potentiated the action of N(6)-cyclopentyladenosine (CPA, 10 nM), a specific adenosine A(1) receptor agonist. Prevention of adenosine accumulation with adenosine deaminase (1 U/ml) did not influence bicuculline-induced potentiation of the effect of 2-chloroadenosine. The potentiation of adenosine A(1)-mediated response by bicuculline was abolished when nitric oxide (NO) synthase was inhibited with nitroarginine (100 microM), and when guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 20 microM). The NO donors, (+/-)-S-nitroso-N-acetylpencillamine (SNAP, 300 microM) and diethylamine NONate diethylammonium salt (DEA/NO, 100 microM), significantly enhanced the inhibitory action of 2-chloroadenosine (150 nM). It is concluded that the blockade of GABA(A) receptors induces a potentiation of adenosine A(1) receptor-mediated inhibitory action, an effect that involves NO acting through guanylyl cyclase. Therefore, endogenous GABA might exert an inhibitory effect over adenosine A(1)-mediated responses in the hippocampus, which may represent a physiologic regulatory mechanism between the two inhibitory mediators.

2-Chloroadenosine↗
PubMed1998

Modulation of oligosynaptic cutaneous and muscle afferent reflex pathways during fictive locomotion and scratching in the cat.

We have compared state-dependent transmission through oligosynaptic (minimally disynaptic) reflex pathways from low-threshold cutaneous and muscle afferents to some flexor and extensor lumbosacral motoneurons during fictive locomotion and scratching in decerebrate unanesthetized cats. As reported in earlier work, oligosynaptic cutaneous excitatory postsynaptic potentials (EPSPs) in flexor digitorum longus (FDL) and inhibitory postsynaptic potentials (IPSPs) in extensor digitorum (EDL) longus motoneurons were enhanced markedly during the early flexion phase of fictive locomotion. We show in this paper that, in contrast, these cutaneous reflex pathways were depressed markedly during all phases of fictive scratching. On the other hand, disynaptic EPSPs produced by homonymous and synergist group I muscle afferents in flexor (tibialis anterior and EDL) motoneurons were present and strongly modulated during both fictive locomotion and scratching. During both actions, these disynaptic group I EPSPs appeared or exhibited the largest amplitude when the motoneuron membrane potential was most depolarized and the parent motor pool was active. There was an interesting exception to the simple pattern of coincident group I EPSP enhancement and motoneuron depolarization. During locomotion, disynaptic group I EPSPs in both FDL and flexor hallucis longus (FHL) motoneurons cells were facilitated during the extension phase, although FDL motoneurons were relatively hyperpolarized whereas FHL cells were depolarized. The reverse situation was found during fictive scratching; group I EPSPs were facilitated in both FDL and FHL cells during the flexion phase when FDL motoneurons were depolarized and FHL cells were relatively hyperpolarized. These observations suggest that the disynaptic EPSPs in these two motor nuclei are produced by common interneurons. Reciprocal disynaptic inhibitory pathways from group Ia muscle afferents to antagonist motoneurons were also active and subject to phase-dependent modulation during both fictive locomotion and scratching. In all but one cell tested, reciprocal disynaptic group Ia IPSPs were largest during those phases in which the motoneuron membrane potential was relatively hyperpolarized and the parent motor pool was inactive. Oligosynaptic PSPs in motoneurons produced by stimulation of the mesencephalic locomotor region (MLR) were modulated strongly during fictive locomotion but were suppressed powerfully throughout fictive scratching. Large cord dorsum potentials generated by MLR stimuli also were suppressed markedly during fictive scratching. These results allow certain inferences about the organization of interneurons in the pathways examined. They also suggest that the central pattern generators that produce fictive locomotion and scratching are organized differently.

Afferent Pathways↗
PubMed1987

Action and location of neuropeptide tyrosine (Y) on hippocampal neurons of the rat in slice preparations.

The action of bath applied NPY (1-1,000 nM) was investigated on hippocampal slices of the rat with extra- and intracellular recording. Neuropeptide Y (NPY) at 10-1,000 nM caused a concentration-dependent, long-lasting reduction of excitatory postsynaptic potentials (EPSPs) in the hippocampal subfield CA1 and the area dentata, and an even stronger reduction of population spikes. Paired pulse experiments with low intensity, stimulation-evoked PSPs showed a marked increase in facilitation in the presence of NPY, indicating a presynaptic action. Spontaneous burst firing of CA1 pyramidal cells in low calcium, high magnesium medium was reduced, indicating a partially postsynaptic inhibitory action of NPY on their dendrites. Intracellular recording from CA1 somata during NPY administration revealed a reduction of the amplitudes of excitatory-inhibitory postsynaptic potential (EPSP-IPSP) sequences in the absence of changes in membrane potential and conductance. Accommodation of firing during long depolarizing pulses and afterhyperpolarizations were unchanged. The innervation pattern of NPY immunoreactive fibers in the same regions was studied in slices adjacent to the ones used for electrophysiology by using antisera against NPY and light and electron microscopy. There is a dense innervation of CA1 by NPY-immunoreactive axons and terminals, particularly in the stratum moleculare. NPY-immunoreactive neurons are present in the stratum oriens and pyramidale. The NPY labeled axons of the stratum moleculare participate in numerous synaptic contacts with the smaller dendritic elements in this layer, many of which belong to pyramidal neurons. These observations provide evidence for a dendritic NPY-immunoreactive innervation of CA1 neurons, which is in keeping with the electrophysiological effects of NPY on pyramidal neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

CLC-3 channels modulate excitatory synaptic transmission in hippocampal neurons.

It is well established that ligand-gated chloride flux across the plasma membrane modulates neuronal excitability. We find that a voltage-dependent Cl(-) conductance increases neuronal excitability in immature rodents as well, enhancing the time course of NMDA receptor-mediated miniature excitatory postsynaptic potentials (mEPSPs). This Cl(-) conductance is activated by CaMKII, is electrophysiologically identical to the CaMKII-activated CLC-3 conductance in nonneuronal cells, and is absent in clc-3(-/-) mice. Systematically decreasing [Cl(-)](i) to mimic postnatal [Cl(-)](i) regulation progressively decreases the amplitude and decay time constant of spontaneous mEPSPs. This Cl(-)-dependent change in synaptic strength is absent in clc-3(-/-) mice. Using surface biotinylation, immunohistochemistry, electron microscopy, and coimmunoprecipitation studies, we find that CLC-3 channels are localized on the plasma membrane, at postsynaptic sites, and in association with NMDA receptors. This is the first demonstration that a voltage-dependent chloride conductance modulates neuronal excitability. By increasing postsynaptic potentials in a Cl(-) dependent fashion, CLC-3 channels regulate neuronal excitability postsynaptically in immature neurons.

Animals↗
PubMed2001

Disynaptic inhibition of omnipause neurons following electrical stimulation of the superior colliculus in alert cats.

We investigated the synaptic organization responsible for the inhibition of omnipause neurons (OPNs) following stimulation of the superior colliculus (SC) in alert cats. Stimulation electrodes were implanted bilaterally in the rostral and caudal SC where a short-pulse train induced small and large saccades, respectively. Effects of single-pulse stimulation on OPNs were examined with intracellular and extracellular recordings. In contrast to monosynaptic excitatory postsynaptic potentials, which were induced by rostral SC stimulation, inhibitory postsynaptic potentials were induced with disynaptic latencies (1.3--1.9 ms) from both the rostral and caudal SC in most OPNs. Analysis of a larger extracellular sample complemented intracellular observations. Monosynaptic activation of OPNs was elicited more frequently from rostral sites than from caudal sites, whereas spike suppression with disynaptic latencies was induced by caudal as well as rostral stimulation with similar frequencies. The results imply that disynaptic inhibition is produced by activation of SC cells that are distributed over wide regions related to saccades of different sizes. We suggest that signals from these neurons initiate a saccadic pause of OPNs through single inhibitory interneurons.

Animals↗
PubMed2004

Estradiol increases delayed, N-methyl-D-aspartate receptor-mediated excitation in the hippocampal CA1 region.

Hippocampal functions, e.g. synaptic plasticity and hippocampal-dependent behavior, are influenced by the circulating levels of ovarian steroids in adult, female rats. The mechanisms underlying this estradiol-dependent modulation, however, are poorly understood. One possibility is that estradiol alters N-methyl-D-aspartate (NMDA)-receptor functioning in the hippocampus. Here, using the in vitro hippocampal slice preparation, we evaluate estradiol-dependent changes in the NMDA receptor- and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated components of excitatory postsynaptic potentials (EPSPs) evoked in CA1 by Schaffer collateral test stimulation. Using established experimental conditions [J Neurosci 17 (1997) 1848], we replicate the observation that estradiol pretreatment of ovariectomized rats increases a pharmacologically isolated NMDA receptor-mediated EPSP evoked by Schaffer collateral stimulation. However, using different conditions that optimize study of this evoked response, the estradiol-dependent increase in the monosynaptic NMDA receptor-mediated EPSP is eliminated. Low-intensity test stimulation of the Schaffer collaterals in this optimized medium reveals a novel, late NMDA receptor-mediated EPSP in CA1 from estradiol-pretreated rats. The mechanism(s) underlying this estradiol-dependent increase in a late, NMDA receptor-mediated EPSP is not known, but enhanced CA1-CA1 excitatory circuitry and glutamate spillover could contribute to this response. We conclude that estradiol pretreatment enhances NMDA receptor function in the female hippocampus by increasing not the monosynaptic, but rather a late NMDA receptor-mediated response. Variations in the magnitude of this late response may well contribute to ovarian steroid-dependent modulation of hippocampal synaptic plasticity.

Animals↗
PubMed2006

In vivo synaptic plasticity in the dentate gyrus of mice deficient in the neural cell adhesion molecule NCAM or its polysialic acid.

The neural cell adhesion molecule NCAM and its associated polysialic acid (PSA) play important roles in synaptic plasticity in the CA1 and/or CA3 regions of the hippocampus in vitro. Here, we address the question of whether NCAM and PSA are involved in regulation of synaptic transmission and plasticity also in vivo at synapses formed by entorhinal cortex axons in the dentate gyrus of mice anaesthetized with urethane. We show that basal synaptic transmission, measured as the slope of field excitatory postsynaptic potentials, was reduced strongly in mice lacking ST8SiaII/STX, the enzyme involved in polysialylation of NCAM in stem cell-derived immature granule cells, but not in mice deficient either in the NCAM glycoprotein or the enzyme ST8SiaIV/PST involved in polysialylation of NCAM in mature neurons. Strikingly, only mice deficient in NCAM, but not in PST or STX, were impaired in long-term potentiation (LTP) induced by theta-burst stimulation, suggesting that LTP in the dentate gyrus depends on the NCAM glycoprotein alone rather than on its associated PSA. As also patterns of synaptic activity during and immediately after induction of LTP were impaired in NCAM-deficient mice, it is likely that induction of LTP requires NCAM. These data are the first to describe that NCAM is necessary for induction of synaptic plasticity in identified synapses in vivo and suggest that polysialylation of NCAM expressed by immature granule cells in the dentate gyrus supports development of basal excitatory synaptic transmission in this region.

Animals↗
PubMed1998

Striatal spiny neurons and cholinergic interneurons express differential ionotropic glutamatergic responses and vulnerability: implications for ischemia and Huntington's disease.

Striatal spiny neurons are selectively vulnerable in Huntington's disease (HD) and ischemia, whereas large aspiny (LA) cholinergic interneurons of the striatum are spared in these pathological conditions. We have investigated whether a different sensitivity to ionotropic glutamatergic agonists might account for this differential vulnerability. Intracellular recordings were obtained from morphologically identified striatal spiny neurons and LA cholinergic interneurons by using a rat brain slice preparation. The two striatal neuronal subtypes had strikingly different intrinsic membrane properties. Both subtypes responded to cortical stimulation with excitatory postsynaptic potentials: these potentials, however, had a different time course and pharmacology in the two classes of cells. Interestingly, membrane depolarizations and inward currents produced by exogenous glutamate receptor agonists (AMPA, kainate, and NMDA) were remarkably larger in spiny neurons than in LA interneurons. Moreover, concentrations of agonists producing reversible membrane changes in LA interneurons caused irreversible depolarizations in spiny cells. Our data suggest that the different physiological responses induced by the activation of ionotropic glutamate receptors may account for the cell type-specific vulnerability of striatal neurons in ischemia and HD.

Animals↗
PubMed2003

Signalling mechanism coupled to 5-hydroxytryptamine4 receptor-mediated facilitation of fast synaptic transmission in the guinea-pig ileum myenteric plexus.

5-hydroxytryptamine (HT)4 receptor agonists stimulate gastrointestinal motility partly by facilitating acetylcholine release from myenteric neurones. However, the signalling mechanisms that couple 5-HT4 receptor activation to increased transmitter release in the myenteric plexus are unknown. We used conventional intracellular electrophysiological methods to record fast excitatory postsynaptic potentials (fEPSPs) from neurones in the guinea-pig ileum myenteric plexus preparation. The substituted benzamide, renzapride, acted at 5-HT4 receptors to facilitate fEPSPs. This response was mimicked by forskolin, an activator of adenylate cyclase. Facilitation of fEPSPs by renzapride and forskolin was not blocked by treating tissues with pertussis toxin (PTX) (2 h, 2 microg mL-1). Facilitation of fEPSPs caused by renzapride was blocked by the non-selective protein kinase inhibitors, staurosporine (1 micromol L-1) and H-8 (30 micromol L-1) and by the selective protein kinase A (PKA) inhibitor, H-89 (10 micromol L-1). These data indicate that 5-HT4 receptors act via a PTX-resistant mechanism to activate PKA. Protein kinase A activation leads to an increase in transmitter release from myenteric nerve terminals and a facilitation of fast excitatory synaptic transmission.

Animals↗