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PubMed1997

Serotonin blocks different patterns of low Mg2+-induced epileptiform activity in rat entorhinal cortex, but not hippocampus.

Low Mg2+-induced epileptiform activity in the entorhinal cortex is characterized by an initial expression of seizure-like events followed by late recurrent discharges. Both these forms of activity as well as the transition between them were blocked by serotonin. In contrast, serotonin had little effect upon the epileptiform activity in areas CA3 and CA1 of the hippocampus. Both forms of epileptiform activity in the entorhinal cortex are sensitive to N-methyl-D-aspartate receptor antagonists and it is shown here that serotonin blocked both types of epileptiform activity through an effective concentration-dependent reduction of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials in deep layer entorhinal cortex cells. Serotonin also prolonged or even prevented the transition between the two types of epileptiform activity and we suggest that this may be through activation of the Na+/K+-ATPase. The resistance of epileptiform activity in CA1 and CA3 to serotonin was most likely related to the inability of serotonin to reduce Schaffer collateral-evoked excitatory postsynaptic potentials. Given the strong serotonergic inputs to both the hippocampus and entorhinal cortex, the differential sensitivity of the two regions to serotonin suggests functional differences. In addition since the late recurrent discharges in the entorhinal cortex are resistant to all clinically used anticonvulsants, serotonin may open new avenues for the development of novel anticonvulsant compounds.

Animals↗
PubMed1994

The nitric oxide--cyclic GMP pathway and synaptic depression in rat hippocampal slices.

The ability of exogenous nitric oxide (NO) to modify synaptic transmission was investigated in area CA1 of the rat hippocampal slice. The NO donors S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (SNOG) depressed field excitatory postsynaptic potentials evoked by low frequency stimulation of the Schaffer collateral-commissural pathway. Upon washout of the NO donors, synaptic transmission rapidly returned to control levels. A similar reversible synaptic depression was produced by SNAP when tetanic stimulation (100 Hz; 1 s) was delivered in its presence. The effect of SNAP was not mimicked by its precursor or breakdown product and was blocked by haemoglobin, indicating that the effect involved NO. Roussin's black salt, a photolabile NO donor, also depressed transiently field excitatory postsynaptic potentials following photolysis. The depression was induced rapidly following a flash of UV light (20 s duration) focused onto the slice using a confocal microscope. The depressant effect of the NO donors on synaptic transmission was mimicked by zaprinast, a specific cGMP-phosphodiesterase inhibitor. Zaprinast depressed to a similar extent both the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and N-methyl-D-aspartate receptor-mediated components of excitatory postsynaptic currents without affecting passive membrane properties, indicating a presynaptic locus of action. SNAP, SNOG and zaprinast all elevated cGMP levels in rat hippocampal slices. Immunocytochemical staining revealed that the cGMP accumulation was mainly in a network of varicose fibres running throughout the CA1 region, consistent with a presynaptic site of action of NO. We conclude that NO, possibly through activation of guanylate cyclase, may be involved in transient presynaptic depression in the CA1 region of the hippocampus.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

The effect of interburst intervals on measures of hippocampal LTP in the freely moving adult male rat.

An important factor in the induction and maintenance of long-term potentiation (LTP) is the tetanization paradigm. This paper presents the changes associated with the induction and maintenance of hippocampal LTP in the freely moving adult male rat, subjected to three different tetanization paradigms. These results indicate that specific LTP measures including (1) synaptic activation, as measured by the slope of the dentate granule cell population excitatory postsynaptic potential, and (2) cellular response, as measured by the dentate population spike amplitude, evoked by single-pulse stimulation of the medial perforant pathway are dependent on the interburst interval of the bursting paradigm commonly used in LTP studies.

Animals↗
PubMed1998

Early impairment and late recovery of synaptic transmission in the rat dentate gyrus following transient forebrain ischemia in vivo.

Ischemic stroke causes various functional deficits in the brain such as memory impairment, and clinical reports have shown that the impaired brain functions may partially recover. However, there has been no experimental model suitable for studying cellular mechanisms of functional recovery following brain ischemia. Therefore, we investigated the long-term influence of transient forebrain ischemia on excitatory synaptic transmission in the rat dentate gyrus, a brain region relatively resistant to ischemia. Fifteen minutes of transient forebrain ischemia produced no apparent histological damage in dentate granule cells, but caused a significant reduction of basal synaptic potentials evoked by perforant path stimulation. Field excitatory postsynaptic potential remained reduced for at least 1 month after ischemia, while population spike recovered to control level in 1 month. The induction of long-term potentiation was also impaired after ischemia, but it showed faster recovery than basal synaptic potentials. In conclusion, we found that synaptic transmission in the dentate gyrus of the rat is impaired following transient forebrain ischemia, but has a potential to recover. These results may provide a good model for studying the mechanisms of impairment and recovery of brain function after transient ischemia.

Animals↗
PubMed1994

Extracellular adenosine concentrations in hippocampal brain slices and the tonic inhibitory modulation of evoked excitatory responses.

Because adenosine is taken up rapidly and metabolized by brain tissue, it has been difficult to establish its true pharmacological potency and, for similar reasons, to determine the basal extracellular concentrations of adenosine in brain. In the present studies, we used several independent pharmacological approaches to estimate these parameters, using the adenosine-mediated inhibition of the field excitatory postsynaptic potential evoked in the CA1 region of rat hippocampal slices as the biological response. The experiments used dipyridamole and S-(4-nitrobenzyl)-6-thioinosine to inhibit adenosine uptake, competitive adenosine receptor antagonists to shift adenosine dose response curves to the right, and corrected for the effect of endogenous adenosine on dose-response curves. These approaches suggested that the EC50 for adenosine for depressing field excitatory postsynaptic potentials is in the range of 600 to 760 nM. Basal extracellular adenosine concentrations in brain slices were then estimated from the responses induced by superfusion with adenosine receptor antagonists. The estimates for the mean endogenous extracellular adenosine concentrations were in the range of 140 to 200 nM, although there was substantial variation in estimates for individual slices. These values fall within the range of estimated extracellular concentrations of adenosine in intact brain based on microdialysis studies, but are significantly below those estimated using biochemical techniques for measurement of total adenosine in brain tissue; this suggests that a substantial fraction of tissue adenosine is in a compartment that does not communicate directly with the extracellular space.

Action Potentials↗
PubMed1997

Interaction between tetanus long-term potentiation and hypoxia-induced potentiation in the rat hippocampus.

Interaction between tetanus long-term potentiation and hypoxia-induced potentiation in the rat hippocampus. J. Neurophysiol. 78: 2475-2482, 1997. The interaction between tetanus-induced long-term potentiation (LTP) and hypoxia-induced potentiation was investigated by performing extracellular recordings in the CA1 region of rat hippocampus using a two-pathway design. Hippocampal slices were placed in an interface chamber containing artificial cerebrospinal fluid (ACSF) solution with high magnesium concentration. Hypoxia was induced by replacing the 5% CO2-95% O2 gas mixture with 5% CO2-95% N2 for 2 min. Tetanus-LTP was induced with 1-s, 100-Hz current pulses. Significant hypoxia-induced potentiation of the slope of the dendritic excitatory postsynaptic potential (EPSP) was found in ACSF containing 2 mM of magnesium 2, 27 +/- 10% (mean +/- SE; n = 16; P < 0.01) with no change in the mean amplitude of the presynaptic volley. All experiments in which a stable control baseline was obtained were used for data analysis. The data show that short episodes (2 min) of hypoxia can induce LTP of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-mediated synaptic transmission. The present study demonstrated that after tetanus-LTP, 33 +/- 3% (n = 10; P < 0.01), hypoxia further potentiated the field EPSP slopes by a mean value of 16 +/- 5% (n = 10; P < 0.05). Moreover, using a two-pathway design, we showed that hypoxia produced similar potentiation in both the control [19 +/- 5%; n = 10; P < 0.01) and tetanus-induced LTP pathway, and the total potentiation produced by a combination of tetanus then hypoxia, 63 +/- 13% (n = 10; p < 0.01), was significantly larger (P < 0.01) than hypoxia alone. These data suggest that hypoxia-induced potentiation is additive with tetanus-LTP. Occlusion experiments were performed to verify whether the mechanisms responsible for hypoxia-induced potentiation are independent of preexisting synaptic levels induced by high-frequency stimulation. Hypoxia produced significant potentiation (23 +/- 7%; n = 7; P < 0.05) after successful occlusion of the LTP pathway. Therefore, because the magnitude of hypoxia-induced potentiation is both independent of preexisting synaptic levels and also additive, synaptic specificity associated with LTP is preserved. The magnitude of tetanus-LTP induced 20 min after hypoxia (15 +/- 4%; n = 10) was significantly smaller (P < 0.01) relative to LTP after normoxic conditions (33 +/- 3%; n = 10). Additionally, hypoxia blocked the transient, robust potentiation occurring during the early phase of LTP induction. This study suggests that although hypoxia modifies neuronal processing by general excitation, synaptic specificity associated with tetanus-LTP still is preserved. However, hypoxia can disrupt neuronal processing by inhibiting new modification of synaptic transmission.

Animals↗
PubMed2003

Tyrosine dephosphorylation and ethanol inhibition of N-Methyl-D-aspartate receptor function.

The inhibitory effect of ethanol on N-methyl-d-aspartate receptors (NMDARs) is well documented in several brain regions. However, the molecular mechanisms by which ethanol affects NMDARs are not well understood. In contrast to the inhibitory effect of ethanol, phosphorylation of the NMDAR potentiates channel currents (Lu, W. Y., Xiong, Z. G., Lei, S., Orser, B. A., Dudek, E., Browning, M. D., and MacDonald, J. F. (1999) Nat. Neurosci. 2, 331-338). We have previously shown that protein kinase C activators induce tyrosine phosphorylation and potentiation of the NMDAR (Grosshans, D. R., Clayton, D. R., Coultrap, S. J., and Browning, M. D. (2002) Nat. Neurosci. 5, 27-33). We therefore hypothesized that the ethanol inhibition of NMDARs might be due to changes in tyrosine phosphorylation of NMDAR subunits. In support of this hypothesis, we found that tyrosine phosphorylation of both NR2A and NR2B subunits was significantly reduced following in situ exposure of hippocampal slices to 100 mm ethanol. Specifically, phosphorylation of tyrosine 1472 on NR2B was reduced 23.5%. These data suggest a possible mechanism by which ethanol may inhibit the NMDAR via activation of a tyrosine phosphatase. Electrophysiological studies demonstrated that ethanol inhibited NMDAR field excitatory postsynaptic potential slope and amplitude to a similar degree as previously reported by our laboratory and others (Schummers, J., Bentz, S., and Browning, M. D. (1997) Alcohol Clin. Exp. Res. 21, 404-408). Inclusion of bpV(phen), a potent phosphotyrosine phosphatase inhibitor, in the recording chamber prior to and during ethanol exposure significantly reduced the inhibitory effect of ethanol on NMDAR field excitatory postsynaptic potentials. Taken together, these data suggest that phosphatase-mediated dephosphorylation of NMDAR subunits may play an important role in mediating the inhibitory effects of ethanol on the N-methyl-D-aspartate receptor.

Animals↗
PubMed2001

Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington's disease transgenic mice.

We examined passive and active membrane properties and synaptic responses of medium-sized spiny striatal neurons in brain slices from presymptomatic (approximately 40 days of age) and symptomatic (approximately 90 days of age) R6/2 transgenics, a mouse model of Huntington's disease (HD) and their age-matched wild-type (WT) controls. This transgenic expresses exon 1 of the human HD gene with approximately 150 CAG repeats and displays a progressive behavioral phenotype associated with numerous neuronal alterations. Intracellular recordings were obtained using standard techniques from R6/2 and age-matched WT mice. Few electrophysiological changes occurred in striatal neurons from presymptomatic R6/2 mice. The changes in this age group were increased neuronal input resistance and lower stimulus intensity to evoke action potentials (rheobase). Symptomatic R6/2 mice exhibited numerous electrophysiological alterations, including depolarized resting membrane potentials, increased input resistances, decreased membrane time constants, and alterations in action potentials. Increased stimulus intensities were required to evoke excitatory postsynaptic potentials (EPSPs) in neurons from symptomatic R6/2 transgenics. These EPSPs had slower rise times and did not decay back to baseline by 45 ms, suggesting a more prominent component mediated by activation of N-methyl-D-aspartate receptors. Neurons from both pre- and symptomatic R6/2 mice exhibited reduced paired-pulse facilitation. Data from biocytin-filled or Golgi-impregnated neurons demonstrated decreased dendritic spine densities, smaller diameters of dendritic shafts, and smaller dendritic fields in symptomatic R6/2 mice. Taken together, these findings indicate that passive and active membrane and synaptic properties of medium-sized spiny neurons are altered in the R6/2 transgenic. These physiological and morphological alterations will affect communication in the basal ganglia circuitry. Furthermore, they suggest areas to target for pharmacotherapies to alleviate and reduce the symptoms of HD.

Action Potentials↗
PubMed1998

Mechanisms underlying the enhancement of excitatory synaptic transmission in basolateral amygdala neurons of the kindling rat.

To elucidate the mechanism underlying epileptiform discharges in kindled rats, synaptic responses in kindled basolateral amygdala neurons in vitro were compared with those from control rats by using intracellular and whole cell patch-clamp recordings. In kindled neurons, electrical stimulation of the stria terminalis induced epileptiform discharges. The resting potential, apparent input resistance, current-voltage relationship of the membrane, and the threshold, amplitude, and duration of action potentials in kindled neurons were not different from those in control neurons. The electrical stimulation of stria terminalis elicited excitatory postsynaptic potentials (EPSPs) and DL-2-amino-5-phosphonopentanoic acid (AP5)-sensitive and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive excitatory postsynaptic currents (EPSCs). The amplitude of evoked EPSPs and of evoked AP5-sensitive and CNQX-sensitive EPSCs were enhanced markedly, whereas fast and slow inhibitory postsynaptic potentials (IPSPs) induced by electrical stimulation of lateral amygdaloid nucleus were not significantly different. The rise time and the decay time constant of the evoked CNQX-sensitive EPSCs were shortened, whereas the rise time of the evoked AP5-sensitive EPSCs was shortened, but the decay time constants were not significantly different. In both tetrodotoxin (TTX)-containing medium and low Ca2+ and TTX-containing medium, the frequency and amplitude of spontaneous EPSCs were increased in kindled neurons. These increases are presumably due to nearly synchronous multiquantal events resulted from the increased probability of Glu release at the nerve terminals. The rise time of evoked CNQX- and AP5-sensitive EPSCs and the decay time constant of evoked CNQX-sensitive EPSCs were shortened, suggesting that excitatory synapses at the proximal dendrite and/or the soma in kindled neurons may contribute more effectively to generate evoked EPSCs than those at distal dendrites. In conclusion, the increases in the amplitudes of spontaneous and evoked EPSCs and in the frequency of spontaneous EPSCs may contribute to the epileptiform discharges in kindled neurons.

2-Amino-5-phosphonovalerate↗
PubMed2002

[Effect of (+/-)-pindolol on the central 5-HT1A receptor by the use of in vivo microdialysis and hippocampal slice preparations].

Although it is suggested that (+/-)-pindolol, a beta-adrenergic/5-HT1A receptor antagonist, may enhance the efficacy of selective serotonin reuptake inhibitors (SSRI), the results of double-blind studies are contradictory and recent animal studies suggest that (+/-)-pindolol may act as a partial agonist to the 5-HT1A receptor. In this study we have investigated the effect of (+/-)-pindolol on both pre- and postsynaptic 5-HT1A receptors using in vivo microdialysis and hippocampal slice preparations. (+/-)-pindolol and flesinoxan, a 5-HT1A receptor full agonist, significantly decreased the extracellular levels of 5-HT in the raphe and prefrontal cortex. The 5-HT and other 5-HT1A receptor agonists, flesinoxan and 8-hydroxy-2- (di-n-propylamino)tetralon (8-OH-DPAT), significantly decreased the population excitatory postsynaptic potential (EPSP) in the CA3-CA1 excitatory synapse in a dose-dependent manner. The effect of 5-HT and other 5-HT1A receptor agonists accompanied the increase in paired-pulse facilitation (ppf) induced by short-interval two stimuli and were reversed by the coadministration of the 5-HT1A receptor agonist, NAN-190, but not by (+/-)-pindolol. (+/-)-pindolol also suppressed the EPSP, but this effect was not reversed by NAN-190. These results suggest that (+/-)-pindolol acts as a partial agonist to the somatodendritic 5-HT1A receptor in the raphe, whereas it may have no action on the postsynaptic 5-HT1A receptor in the hippocampus.

Animals↗
PubMed1996

Serotonergic modulation of evoked responses in turtle cerebellar Purkinje cells.

1. Immunocytochemical studies of the turtle brain revealed the presence of serotonin (5-hydroxytryptamine, 5-HT) immunoreactive (5-HT-ir) processes in the granule and Purkinje cell layers, but not in the molecular layer (ML), of the cerebellar cortex. Immunoreactive axonal profiles were present throughout the granule cell layer (GCL) where they generally coursed in an anteroposterior direction and could frequently be seen to ascend toward the Purkinje cell layer (PCL). Occasional 5-HT-ir processes were observed adjacent to Purkinje cell somata. 2. The effects of exogenously applied serotonin on mossy fiber and parallel fiber evoked responses in turtle Purkinje cells were examined by use of intrasomatic and intradendritic recordings in an intact cerebellar preparation in vitro. 3. Bath application of serotonin (0.2-1.0 microM) produced a dose-dependent reduction in Purkinje cell membrane resistance, which was not correlated with changes in postsynaptic response amplitude. At 5-HT concentrations > 1.0 microM (0.01-5 mM), resistance values returned to control levels. No consistent changes in spike width or postspike afterhyperpolarization were seen in response to serotonin application, nor were endogenous pacemaker-like discharges affected. Firing rate, assessed as threshold response to depolarizing current injection (0.3-1.0 nA, 1 s duration), was increased in 51% and decreased in 40% of cells tested. 4. Single stimuli delivered to either the cerebellar peduncle or the GCL resulted in the activation of fast excitatory postsynaptic potentials (fEPSP). These responses were dose dependently reduced in amplitude by bath application of serotonin (0.2-1.0 microM). At concentrations ranging from 10 to 100 microM, the response amplitude following agonist application plateaued at approximately 70% of control value. With higher dose applications (0.5-5 mM) of serotonin, the response amplitude exhibited a steep reduction (from 65-10% of control value). 5. Brief trains of stimuli (5 stimuli, 50 Hz) delivered to either the cerebellar peduncle or the GCL resulted in the activation of slow excitatory postsynaptic potentials (sEPSP). The peak amplitude of this response was unaffected by bath application of serotonin at concentrations ranging from 0.2 to 100 microM. At higher concentrations (0.5-5 mM), the sEPSP peak amplitude was dose-dependently reduced, with the largest amplitude reduction seen after peduncular stimulation. 6. It is suggested that serotonin acts as a modulator of fast excitatory synaptic activity in the cerebellar cortex, while exerting little affect on slow excitatory events. The fact that serotonin preferentially affects fast excitatory transmission may have important implications for the integration of incoming sensory signals at both the granule and Purkinje cell level.

Animals↗
PubMed1998

Frequency potentiation in the medial cortex of young turtle brains in vitro.

Turtle brains have a relatively primitive cortex. Glutamate receptors in the cortex of turtles include N-methyl-D-aspartate (NMDA) and DL-alpha-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA). Our aim was to determine whether the medial cortex in turtles, like the cortex and hippocampus in mammals exhibits frequency potentiation, a non-lasting form of synaptic plasticity, and, if so, to identify the involved receptors. Our results indicate that (1) the medial cortex exhibits this phenomenon with septal stimulation at 2 Hz, the frequency with maximum power spectral density in the electrocorticogram of turtles, showing an increase in both the excitatory postsynaptic potential and the evoked potential amplitudes; (2) the frequency potentiation of the medial cortex in turtles is mediated by AMPA type glutamate receptors; (3) the dynamics of frequency potentiation development in turtles show a number of differences from that in mammals. In summary, the cortex in this group of reptiles exhibits a functional trait of the cortex in mammals that is related to learning and memory; this trait, frequency potentiation, may have appeared as an independent specialization in both groups.

Animals↗
PubMed2005

Transmission between type II hair cells and bouton afferents in the turtle posterior crista.

Synaptic activity was recorded with sharp microelectrodes during rest and during 0.3-Hz sinusoidal stimulation from bouton afferents identified by their efferent-mediated inhibitory responses. A glutamate antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) decreased quantal size (qsize) while lowering external Ca(2+) decreased quantal rate (qrate). Miniature excitatory postsynaptic potentials (mEPSPs) had effective durations (qdur) of 3.5-5 ms. Their timing was consistent with Poisson statistics. Mean qsizes ranged in different units from 0.25 to 0.73 mV and mean qrates from 200 to 1,500/s; there was an inverse relation across the afferent population between qrate and qsize. qsize distributions were consistent with the independent release of variable-sized quanta. Channel noise, measured during AMPA-induced depolarizations, was small compared with quantal noise. Excitatory responses were larger than inhibitory responses. Peak qrates, which could approach 3,000/s, led peak excitatory mechanical stimulation by 40 degrees . Quantal parameters varied with stimulation phase with qdur and qsize being maximal during inhibitory stimulation. Voltage modulation (vmod) was in phase with qrate and had a peak depolarization of 1.5-3 mV. On average, 80% of vmod was accounted for by quantal activity; the remaining 20% was a nonquantal component that persisted in the absence of quantal activity. The extracellular accumulation of glutamate and K(+) are potential sources of nonquantal transmission and may provide a basis for the inverse relation between qrate and qsize. Comparison of the phases of synaptic and spike activity suggests that both presynaptic and postsynaptic mechanisms contribute to variations across afferents in the timing of spikes during sinusoidal stimulation.

Action Potentials↗
PubMed1985

Abnormal neuronal excitability in hippocampal slices from kindled rats.

To determine if electrophysiological properties of hippocampal pathways are altered in kindled rats, extracellular recordings were made from hippocampal slices of rats kindled in the lateral entorhinal cortex and compared with those from implanted but unstimulated controls. Studies were made either 24 h or 28 days after the last kindled seizure and done in normal (3.5 mM) or elevated (7 mM) K+. The preparation of slices, data accumulation, and data analyses were done blind. One day or 28 days after the last kindled seizure, the proportion of slices with spontaneous epileptiform bursts recorded from the CA2/3 region in elevated K+ was significantly (P less than 0.001) increased in the kindled animals. The frequency of spontaneous burst firing was also increased and reached significance (P less than 0.02) at 28 days following the last kindling stimulus. One day after the last kindling stimulus, paired-pulse (GABAergic) inhibition in the CA1 region was decreased (P less than 0.001). Several measures suggested an increased synaptic inhibition in the dentate gyrus of slices from the kindled groups 1 day after kindling. Paired-pulse inhibition was increased (P less than 0.01), the current required to evoke a near-threshold population spike was increased (P less than 0.05), and the population spike amplitude was reduced for a given field excitatory postsynaptic potential (EPSP) (P less than 0.01). Twenty-eight days after the last kindling stimulus, however, paired-pulse inhibition in the dentate was slightly less in slices from kindled rats (P less than 0.005). In other respects the CA1 and dentate regions did not differ between kindled and control groups within 24 h of the last stage V seizure. Thus the maximum amplitudes of presynaptic fiber volley, population spike, and field-excitatory postsynaptic potential (EPSP) slope, and the number of population spikes evoked by a near-maximally effective afferent stimulus, were unchanged. In the CA1 region the input-output curve of field EPSP versus population spike, and the current intensity required to evoke a near-threshold population spike were also unchanged. In addition, no spontaneous bursts were recorded from CA1 in 3.5 mM K+. We conclude that either synapses or neurons intrinsic to the hippocampus are altered by kindling stimuli applied outside this brain area. The transient increase in inhibition in the dentate gyrus suggests that it may reflect a compensatory reaction to kindled seizures. In contrast, the long-lasting (at least 28 days) increase in burst firing in CA2/3 may represent a mechanism for the initiation or propagation of kindled seizures.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

The identification of the sympathetic neurons innervating the hamster submandibular gland and their electrophysiological membrane properties.

The neuron innervating the hamster submandibular (SM) gland was identified in the superior cervical ganglion (SCG) in vitro by recording the antidromic response using the intracellular recording technique. After the cellular response was recorded, methylene blue was injected iontophoretically into the neuron from the recording electrode, and the location of the cell soma was determined. The salivatory neurons of the SM gland were in the small- to medium-sized group of the entire cell population of the SCG. The cell size was 36.3 x 24.4 microm (mean, n=45). The postganglionic fibers were entirely unmyelinated (mean: 0.34 m/sec at 28-30 degrees C, n=141). Eighty-seven percent of the cells were distributed in the central one-third of area between the external carotid nerve origin and the caudal pole in the SCG. The resting membrane potential, membrane input resistance, membrane time constant and membrane input capacitance of the salivatory neuron were as follows: -49.2+/-7.6 mV (n=102), 52.9+/-23.6 Mohms (n=71), 8.0+/-3.4 msec (n=71) and 147+/-50 pF (n=71). Fast- and slow-excitatory postsynaptic potentials (EPSPs) were evoked, but not slow-inhibitory postsynaptic potentials (IPSPs). The fast EPSP was 13.1+/-5.7 mV in amplitude and 46.2+/-17.1 msec in duration (n=35). The slow EPSP (20 Hz, 5 sec) was 6.9+/-11 .9 mV in amplitude and 101+/-43 sec in duration (n=16). The directly-evoked spike was 63.0+/-11.9 mV in amplitude and 5.9+/-1.3 msec in duration (n=54). The spike after-hyperpolarization (AHP) was 12.5+/-3.5 mV in amplitude and 353+/-161 msec in duration. Na+ and Ca+ channels were involved in the spike generation. The voltage-dependent K+ channels (delayed rectifier), A channels and rapidly Ca2+-activated K+ channels (BK channels) regulated the spike-falling phase. The delayed rectifiers, A channels, and BK and SK (slowly Ca2+-activated) channels were involved in generation of spike-AHP. Muscarine suppressed the Ca2+ component of spike via muscarinic receptors.

4-Aminopyridine↗
PubMed2002

Endogenous neurokinins facilitate synaptic transmission in guinea pig airway parasympathetic ganglia.

Neurokinin-containing nerve fibers were localized to guinea pig airway parasympathetic ganglia in control tissues but not in tissues pretreated with capsaicin. The purpose of the present study was to determine whether neurokinins, released during axonal reflexes or after antidromic afferent nerve stimulation, modulate ganglionic synaptic neurotransmission. The neurokinin type 3 (NK(3)) receptor antagonists SB-223412 and SR-142801 inhibited vagally mediated cholinergic contractions of bronchi in vitro at stimulation voltages threshold for preganglionic nerve activation but had no effect on vagally mediated contractions evoked at optimal voltage or field stimulation-induced contractions. Intracellular recordings from the ganglia neurons revealed that capsaicin-sensitive nerve stimulation potentiated subsequent preganglionic nerve-evoked fast excitatory postsynaptic potentials. This effect was mimicked by the NK(3) receptor agonist senktide analog and blocked by SB-223412. In situ, senktide analog markedly increased baseline tracheal cholinergic tone, an effect that was reversed by atropine and prevented by vagotomy or SB-223412. Comparable effects of intravenous senktide analog on pulmonary insufflation pressure were observed. These data highlight the important integrative role played by parasympathetic ganglia and indicate that activation of NK(3) receptors in airway ganglia by endogenous neurokinins facilitates synaptic neurotransmission.

Animals↗
PubMed2004

The actions of a charged melatonin receptor ligand, TMEPI, and an irreversible MT2 receptor agonist, BMNEP, on mouse hippocampal evoked potentials in vitro.

We have previously determined that melatonin modulates hippocampal synaptic transmission in a biphasic way: an initial depression was followed by a recovery/amplification phase. Here we describe the influence of two novel melatonin receptor ligands, BMNEP (N-bromoacetyl-2-iodo-5-methoxytryptamine) and TMPEI (N-[2-(2-Trimethylammoniumethyleneoxy-7-methoxy)ethyl]propionamide iodide), on the population spike (PS) and excitatory postsynaptic potentials (EPSP) recorded from mouse hippocampal slices. BMNEP, which specifically alkylates and constitutively activates the MT2 melatonin receptor, mimicked the first phase of melatonin's action by irreversibly depressing both the PS and EPSP. TMPEI, a charged ligand of plasma membrane melatonin receptors, amplified those potentials in a manner similar to the effect of melatonin observed during the second, recovery phase. Melatonin had no influence on the potentials amplified by the action of TMPEI. Our results suggest that the biphasic, receptor-dependent action of melatonin and its analogs modulates the efficiency of the hippocampal glutamergic synapse and is most likely mediated through two different, sequentially occurring mechanisms.

5-Methoxytryptamine↗
PubMed2002

Impaired M-current and neuronal excitability.

PURPOSE: Benign familial neonatal convulsions (BFNC), a hereditary epilepsy, occurs specifically in newborns and remits spontaneously after this period. Several mutations of either KCNQ2 or KCNQ3, members of the KCNQ-related K+-channel (KCNQ-channel) family, were identified as a cause of BFNC. Such mutations impair KCNQ-related M- current, an element of the inhibitory system in the central nervous system (CNS), and therefore are thought to result in neuronal hyperexcitability. METHODS: To clarify the pathogenesis of BFNC, this study investigated the effects of the KCNQ channel on propagation of neuronal excitability using a 64-channel multielectrode dish (MED64) system for novel two-dimensional monitoring of evoked field potentials including fiber volley (FV) and field excitatory postsynaptic potential (fEPSP). RESULTS: Dup996, a selective KCNQ-channel inhibitor, did not affect the amplitude of FV or fEPSP, but enhanced the FV and fEPSP propagation. The gamma-aminobutyric acid (GABA)A-receptor antagonist, bicuculline, enhanced their propagation, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/glutamate-receptor antagonist, DNQX, reduced both amplitude and propagation of fEPSP without affecting those of FV. Under the condition of GABAA-receptor blockade by bicuculline, Dup996 enhanced the amplitude of fEPSP and propagation of FV and fEPSP without affecting the amplitude of FV. Dup996 enhanced the stimulating effects of bicuculline on the propagation and amplitude of FV and fEPSP, but it did not affect the inhibiting effects of DNQX. CONCLUSIONS: These results suggest that the occurrence of BFNC cannot be produced by KCNQ-channel dysfunction alone but by reciprocal action between impaired KCNQ channel and the other unknown.

Age Factors↗