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Serotonin inhibits the induction of long-term potentiation in rat primary visual cortex.

1. The effect of serotonin (5-hydroxytryptamine; 5-HT) on the induction of long-term potentiation (LTP) in rat visual cortex was investigated by using slice preparations in vitro. 2. Bath application of 5-HT (0.1-10 microM) did not affect the baseline synaptic potentials evoked by single-pulse test stimulation, but inhibited the induction of LTP in a concentration-dependent manner. 3. The effect of 5-HT was blocked by the 5-HT1 receptor antagonist pindolol or the 5-HT2,7 receptor antagonist ritanserin, but not by the 5-HT3,4 receptor antagonist MDL72222. 4. These results suggest that 5-HT plays a role in suppressing the induction of LTP in the rat visual cortex.

Animals↗

Activity-dependent changes of tissue resistivity in the CA1 region in vivo are layer-specific: modulation of evoked potentials.

We have investigated the spatial map of tissue resistivity across CA1 layers in vivo, its modifications during repetitive orthodromic activity, and the influence of this factor on the shaping of population spikes. Measurement of tissue resistance was made by a high-spatial-resolution three-electrode method. A computer network of equivalent resistors aided theoretical analysis. Tissue resistivity was homogeneous within the basal and apical dendritic trees (260+/-4.5 and 287+/-2.6 Omega cm, respectively). In the stratum pyramidale we found a sharply delimited high-resistivity (643+/-35 Omega cm) band approximately 20 microm wide. Resistivity in slices was approximately 30% higher than in vivo. Computer analysis indicated that the high-resistance somatic layer has a strong influence on the somatic and proximal dendritic contribution to the shaping of population spikes, and reduces volume propagation of currents between dendritic trees. Repetitive orthodromic activation at the theta frequency (4-5 Hz, 20-30 s) caused a stereotyped cycle of field potentials and layer-specific changes of resistivity. Initially (approximately 10 s), long-lasting field excitatory postsynaptic potentials and multiple somatodendritic population spikes developed, and resistivity gradually increased in all layers at a similar rate (period average: 11%). Subsequently, the long-lasting field excitatory synaptic potential subsided and dendritic spike generators were strongly reduced, but multiple somatic spikes remained. Concurrently, the resistivity reached a plateau in all dendritic layers but continued to increase in the somatic layer for about 10-15 s (20% average and up to 50% maximum). Recovery required approximately 60 s. The orthodromic somatic population spike increased variably during stimulation (up to 60%). Using local resistivity changes for correction, supernormal increments of the population spikes were offset, but not totally, uncovering several sub- and supernormal phases that were partially related to changes in dendritic population spike. These resistivity-independent modulations of the somatic population spike are caused by variable volume spread from dendritic spike currents and changed somatic contribution of firing units. This report demonstrates that the strong heterogeneity in the stratum pyramidale is an important factor shaping and modulating the population spike. The different regional rates of resistivity variation force the independent correction of local evoked potentials. We show that not doing so may cause bulk errors in the interpretation of, for instance, field potential ratios widely used to measure the population excitability. The present results underscore the importance of checking variations in recording conditions, which are inherent in most experimental protocols.

Action Potentials↗

Calcium calmodulin-dependent protein kinase IV is required for fear memory.

The ability to remember potential dangers in an environment is necessary to the survival of animals and humans. The cyclic AMP responsive element binding protein (CREB) is a key transcription factor in synaptic plasticity and memory consolidation. We have found that in CaMKIV(-/-) mice--which are deficient in a component of the calcium calmodulin-dependent protein kinase (CaMK) pathway, a major pathway of CREB activation--fear memory, but not persistent pain, was significantly reduced. CREB activation by fear conditioning and synaptic potentiation in the amygdala and cortical areas was reduced or blocked. We propose that cognitive memory related to a noxious shock can be disassociated from behavioral responses to tissue injury and inflammation.

Amygdala↗

Functional and morphological changes in the hippocampal neuronal circuits associated with epileptic seizures.

PURPOSE: We review what is currently known about functional and morphologic plasticity of hippocampal neuronal circuits in animal epilepsy models. RESULTS: Perforant-path kindling has been shown to enhance excitatory synaptic transmission in the dentate gyrus significantly, and this enhancement has lasted for > or =1 month after kindling. However, in our rapid kindling experiment with an interstimulus interval of 5 min, perforant-path kindling resulted in behavioral convulsions and prolonged the afterdischarge duration, but dentate synaptic transmission remained depressed during kindling. CONCLUSIONS: These results indicate that kindling-induced synaptic potentiation is not necessary for kindling development. Conversely, epileptic seizures have led to the anomalous sprouting of mossy fibers, a process thought to induce hyperexcitation of granule cells. We conclude that the sprouting of mossy fibers did not play a critical role in kindling, because we observed no significant correlation between the mossy fiber sprouting and kindling development. Epileptic seizures also have been shown to increase gamma-aminobutyric acid (GABA)A receptor-mediated inhibition during interictal periods. Although this strengthening of GABAergic inhibition is likely to be a defensive measure against seizure initiation, some studies have suggested that another type of GABAergic response facilitates seizure activity. The possibility of GABAA receptor-mediated excitation during ictal periods is theoretically examined.

Animals↗

ELECTRICAL PROPERTIES OF HYPOTHALAMIC NEUROENDOCRINE CELLS.

Goldfish hypothalamic neuroendocrine cells have been investigated with intracellular recordings. The cells showed resting potentials of 50 mv and action potentials up to 117 mv followed by a long lasting and prominent diphasic hyperpolarizing afterpotential. The action potential occurred in two steps indicating sequential invasion. "Total" neuron (input) resistance was measured to be 3.3 x 10(7) ohm and total neuron time constant was 42 msec. Orthodromic volleys, produced by olfactory tract stimulation, generated graded excitatory postsynaptic potentials. These neuroendocrine cells seem, therefore, to have electrical membrane properties that are similar to those of other central neurons. Antidromic volleys (pituitary stimulation) produced inhibitory post-synaptic potentials whose latency was only slightly longer than that of the antidromic spike indicating the presence of recurrent collaterals. This finding suggests that the concept of the neuroendocrine cell as a neuron whose axon forms contacts only on blood vessels and not on other neurons or effector cells is too restrictive. Perfusion of the gills with dilute (0.3 per cent) sea water produced an inhibition of spontaneous activity. This inhibition is discussed in relation to recent work which demonstrates that goldfish hypothalamic hormones facilitate Na(+) influx across the gill membrane.

Action Potentials↗

Properties of excitatory synaptic responses in fast-spiking interneurons and pyramidal cells from monkey and rat prefrontal cortex.

In the prefrontal cortex (PFC) during working memory tasks fast-spiking (FS) interneurons might shape the spatial selectivity of pyramidal cell firing. In order to provide time control of pyramidal cell activity, incoming excitatory inputs should excite FS interneurons more vigorously than pyramidal cells. This can be achieved if subthreshold excitatory responses of interneurons are considerably stronger and faster than those in pyramidal neurons. Here we compared the functional properties of excitatory post-synaptic potentials (EPSPs) between pyramidal cells and FS interneurons in slices from monkey dorsolateral PFC and rat prelimbic cortex. Miniature, unitary (in connected pairs or by minimal stimulation) and compound (evoked by electrical stimulation of the white matter) EPSPs were recorded in whole cell mode. We found that EPSPs were significantly larger and faster in FS interneurons than those recorded from pyramidal cells, consistent with the idea of more efficient recruitment of FS interneurons compared to pyramidal neurons. Similar results were obtained in monkey and rat PFC, suggesting a stable role of FS interneurons in this circuitry across species.

Action Potentials↗

Feedforward inhibitory connections from multiple thalamic cells to multiple regular-spiking cells in layer 4 of the somatosensory cortex.

Thalamocortical (TC) cells in the ventrobasal thalamus make direct excitatory connections with regular-spiking (RS) cells in layer 4 of the somatosensory cortex, but also make disynaptic feedforward inhibitory connections with the RS cells by layer 4 fast-spiking (FS) cells. In this study, we investigated connection rules of the feedforward inhibitory circuit from multiple TC cells to multiple RS cells, at the level of synaptic potentials. Using thalamocortical brain slices of young mice (postnatal days 12-16), we made simultaneous patch-clamp recordings from three adjacent cortical cells (two RS cells and one FS cell), combined with minimal stimulation of presumed single TC fibers. We found that nearly all (97%) of TC fibers, which generated excitatory inputs onto RS cells, also generated divergent excitatory inputs onto adjacent FS cells. Some 44% of TC fibers generated divergent excitatory inputs onto adjacent pairs of RS cells. We then combined the triple patch-clamp recording with multisite (two to three) minimal stimulation of single TC fibers and found that 86% of FS cells received convergent inputs from all of the stimulated TC fibers. We also found that 68% of FS cells generated divergent inhibitory inputs onto adjacent pairs of RS cells. The results indicate that spikes in TC cells, which excite RS cells, also excite adjacent FS cells with high fidelity. The results also indicate that FS cells receive convergent excitatory inputs from multiple TC cells and then send divergent inhibitory outputs to multiple RS cells.

Action Potentials↗

The spatiotemporal transfer function of crayfish lamina monopolar neurons.

1. The graded, synaptic potentials of first-order visual interneurons (lamina monopolar cells) were examined with intracellular recordings. The spatiotemporal properties were characterized with drifting sine wave gratings and annuli. 2. Annulus-elicited inhibition is maximal for annulus-test pulse intervals of approximately 140 ms and declines exponentially. The inhibition declines with increasing annular internal radii (ri). 3. Grating responses were examined with respect to spatial and temporal frequency. The gratings elicit sinusoidal signals that are approximately linear with contrast. 4. Variations in spatial frequency produce response functions with a low-pass or modest band-pass characteristic, which are described by a difference of Gaussians sensitivity profile. The central Gaussian approximates the sensitivity profile of photoreceptors. The inhibitory Gaussian is similar to the inhibitory field estimated with annulus pulses. The peak of the inhibitory Gaussian is approximately 18% of the peak excitatory Gaussian. 5. Variations in temporal frequency generally produce transfer functions with a band-pass characteristic and a peak at 1.0 Hz. These data were described by a difference of exponentials function convolved with a low-pass filter that approximates the photoreceptor response. The inhibitory time course estimated from these data was similar to that of the annulus measurements. 6. The spatiotemporal properties of lateral inhibition are consistent with inhibitory action by the lamina amacrine neurons. The proposed model is spatiotemporally inseparable and nonrecurrent. 7. Eleven of 20 monopolar cells tested exhibited a strong orientation preference with a bias to the vertical. Photoreceptors exhibit little or no orientation preference.

Animals↗

Limbic kindling and animal behavior--implications for human psychopathology associated with complex partial seizures.

The latest thinking concerning the neural mechanisms of limbic kindling is briefly reviewed. It is proposed that three types of lasting neural changes accompany the increases in epileptogenicity resulting from repetitive electrical stimulation of the limbic system in animals. Two of these, long-lasting synaptic potentiation and increased susceptibility to failure, under high drive, of neurotransmitter systems antagonistic to seizure expression, are proposed to underly the lasting interictally maintained changes in species-characteristic behavior in animals. It is proposed that similar processes may occur in some humans afflicted with complex partial epilepsy, and that these processes could explain the paradoxical relationship between seizures and psychopathology.

Aggression↗

Calcium and neuronal plasticity.

The proposed involvement of free intracellular calcium concentration ([Ca]i) in neuronal plasticity is examined. While it is generally believed that a rise of [Ca]i is necessary for the triggering of long-term modification of synaptic connections, there are many unresolved issues related to this dogma; it is not entirely clear what is the source of the elevated calcium, how much of a calcium rise is sufficient to produce the synaptic potentiation, where and for how long, and what are the relevant chemical consequences of the transient rise of [Ca]i. It is generally believed that the dendritic spine is the locus of synaptic modification, yet little evidence exists to support this view. High resolution calcium imaging studies may contribute to the clarification of some key issues in the field of neuronal plasticity.

Animals↗

Kindling induces transient fast inhibition in the dentate gyrus--CA3 projection.

The granule cells of the dentate gyrus (DG) send a strong glutamatergic projection, the mossy fibre tract, toward the hippocampal CA3 field, where it excites pyramidal cells and neighbouring inhibitory interneurons. Despite their excitatory nature, granule cells contain small amounts of GAD (glutamate decarboxylase), the main synthetic enzyme for the inhibitory transmitter GABA. Chronic temporal lobe epilepsy results in transient upregulation of GAD and GABA in granule cells, giving rise to the speculation that following overexcitation, mossy fibres exert an inhibitory effect by release of GABA. We therefore stimulated the DG and recorded synaptic potentials from CA3 pyramidal cells in brain slices from kindled and control rats. In both preparations, DG stimulation caused excitatory postsynaptic potential (EPSP)/inhibitory postsynaptic potential (IPSP) sequences. These potentials could be completely blocked by glutamate receptor antagonists in control rats, while in the kindled rats, a bicuculline-sensitive fast IPSP remained, with an onset latency similar to that of the control EPSP. Interestingly, this IPSP disappeared 1 month after the last seizure. When synaptic responses were evoked by high-frequency stimulation, EPSPs in normal rats readily summate to evoke action potentials. In slices from kindled rats, a summation of IPSPs overrides that of the EPSPs and reduces the probability of evoking action potentials. Our data show for the first time that kindling induces functionally relevant activity-dependent expression of fast inhibition onto pyramidal cells, coming from the DG, that can limit CA3 excitation in a frequency-dependent manner.

2-Amino-5-phosphonovalerate↗

Metabotropic glutamate receptors and cell-type-specific vulnerability in the striatum: implication for ischemia and Huntington's disease.

Differential sensitivity to glutamate has been proposed to contribute to the cell-type-specific vulnerability observed in neurological disorders affecting the striatum such as Huntington's disease (HD) and global ischemia. Under these pathological conditions striatal spiny neurons are selectively lost while large aspiny (LA) cholinergic interneurons are spared. We studied the electrophysiological effects of metabotropic glutamate receptor (mGluR) activation in striatal spiny neurons and LA interneurons in order to define the role of these receptors in the pathophysiology of the striatum. DCG-IV and L-SOP, agonists for group II and III mGluRs respectively, produced a presynaptic inhibitory effect on corticostriatal glutamatergic excitatory synaptic potentials in both spiny neurons and LA interneurons. Activation of group I mGluRs by the selective agonist 3,5-DHPG produced no detectable effects on membrane properties and glutamatergic synaptic transmission in spiny neurons while it caused a slow membrane depolarization in LA interneurons coupled to increased input resistance. In combined electrophysiological and microfluorometric recordings, 3,5-DHPG strongly enhanced membrane depolarizations and intracellular Ca2+ accumulation induced by NMDA applications in spiny neurons but not in LA interneurons. Activation of protein kinase C (PKC) by phorbol 12,13-diacetate mimicked this latter action of 3,5-DHPG while the facilitatory effect of 3,5-DHPG was prevented by calphostin C, an inhibitor of PKC. These data indicate that a positive interaction between NMDA receptors and group I mGluRs, via PKC activation, is differently expressed in these two neuronal subtypes. Our data also suggest that differential effects of the activation of group I mGluRs, but not of group II and III mGluRs, might partially account for the selective vulnerability to excitotoxic damage observed within the striatum.

Animals↗

Segregation of NMDA and non-NMDA receptors at separate synaptic contacts: evidence from spontaneous EPSPs in Xenopus embryo spinal neurons.

Many excitatory amino acid (EAA)-mediated synaptic potentials are dual-component as a result of the simultaneous activation of N-methyl-D-aspartate (NMDA) and non-NMDA receptor subtypes, the two major classes of EAA receptor in vertebrates. This raises the question of whether the two receptor types are located separately or together at individual synaptic contacts. Support for the segregation of NMDA and non-NMDA receptors in discrete anatomical patches arises from the observation that the fast and slow components of dual-component potentials mediated via NMDA and non-NMDA receptor types can fail independently. We have obtained further support for this by investigating the spontaneous release of EAA neurotransmitter at sensory synapses in the spinal cord of Xenopus laevis embryos. We report the occurrence of spontaneous TTX-resistant EPSPs in sensory interneurons that are mediated by EAA receptors. These spontaneous potentials share the same pharmacological sensitivities as EPSPs evoked by skin sensory afferents, being blocked by kynurenic acid and reduced by (+-)-2-amino-5-phosphonovaleric acid (APV). The spontaneous EPSPs differ from evoked EPSPs in their time courses: while evoked EPSPs are almost exclusively of the dual-component variety, the spontaneous EPSPs are predominantly either fast or slow. These data suggest that spontaneous EPSPs reflect release of EAA neurotransmitter at synaptic contacts overlying homogeneous populations of either NMDA or non-NMDA receptors. Their relatively large size, up to 50% or more of the amplitude of unitary EPSPs evoked by stimulation, also suggests that synapses between skin afferents and sensory interneurons may comprise relatively few points of synaptic contact.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Modulation of synaptic efficacy in field CA1 of the rat hippocampus by forskolin.

Activation of cAMP-dependent protein kinase (kinase A) has recently been shown to enhance responses evoked by stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in cultured hippocampal pyramidal neurons. Here we report results of experiments designed to determine if activation of the cAMP cascade potentiates synaptic strength in field CA1 of rat hippocampal slices. We find that bath application of the direct adenylate cyclase activator forskolin (50 microM) enhances the field excitatory postsynaptic potential (EPSP) slope and population spike amplitude evoked by stimulation of Schaffer/commissural afferents. This effect is potentiated by the phosphodiesterase inhibitor and adenosine receptor antagonist 3-isobutyl-1-methylxanthine (IBMX). The enhancement produced by forskolin is suppressed in the presence of adenylate cyclase inhibitors and is not mimicked by the inactive forskolin analogue 1,9-dideoxyforskolin, indicating that, indeed, activation of adenylate cyclase mediates the effects of forskolin in field CA1. Our observations support the idea that changes in intracellular cAMP levels can modulate synaptic efficacy of excitatory glutamatergic synapses in the mammalian hippocampus.

1-Methyl-3-isobutylxanthine↗

The action of calcium at spinal neurones of the frog.

1. The action of Ca on membrane excitability and synaptic transmission at motoneurones of the isolated spinal cord of the frog has been studied.2. Impulse propagation along presynaptic fibres was unaffected by [Ca] in the range of 0-10 mM in the presence of 1 mM-Mg.3. Motoneurone membrane excitability was within normal ranges when the cord was bathed in low or 0 Ca solutions containing 1 mM-Mg but was depressed in 5 or 10 mM-Ca solutions.4. Spontaneous miniature synaptic potentials were recorded in the presence of tetrodotoxin. The frequencies were reduced but not abolished in the absence of bath Ca, but were increased greater than twofold in 5 or 10 mM-Ca in comparison to those in normal Ringer solution (1 mM-Ca).5. Iontophoretic application of Ca both near to and remotely from the intracellular recording site (presumably in the soma) caused facilitation of elicited post-synaptic potentials.6. It is concluded that the action of Ca at these central synapses is identical to that described at the neuromuscular junction.

Action Potentials↗

Inhibitory action of serotonin in CA1 hippocampal neurons in vitro.

The ionic mechanism of the inhibitory effect of serotonin was investigated in vitro in the CA1 region of the rat hippocampus by extra- and intracellular recordings. Local or bath applications of serotonin induced a long-lasting reduction of extracellularly recorded synaptic potentials and orthodromic population spikes without affecting the afferent volley or the antidromic population spike. Serotonin can also reduce the frequency of occurrence of spontaneous excitatory and inhibitory postsynaptic potentials without any reduction of input resistance of the pyramidal neuron. During the response to serotonin, the conductance increase evoked by GABA, the inhibitory neurotransmitter, was not changed. A direct postsynaptic effect of serotonin was demonstrated: local or bath applications of serotonin induced a tetrodotoxin-resistant hyperpolarization and conductance increase. The conductance change was not reduced by manual clamp of the neurons to the control resting membrane potential; therefore, a possible involvement of the sodium-potassium electrogenic pump is unlikely. When neurons were loaded with chloride, serotonin could still induce a hyperpolarization with an apparent reversal more negative than the resting membrane potential. When neurons were loaded with caesium, the hyperpolarization and the conductance increase evoked by serotonin were blocked. It is therefore concluded that serotonin increases potassium permeability. Similar effects were induced by a 5-HT1A ligand. The slow after hyperpolarization was reduced by serotonin; the calcium spike was reduced at the same time. In caesium loaded neurons, the spike duration was not modified by serotonin. In the presence of extracellular caesium (4-5 mM), the serotonin-induced hyperpolarization and the conductance change were blocked, but the effect of serotonin on calcium spikes persisted. Tetraethylammonium (5-10 mM) or 4-aminopyridine (0.5 mM) had no effect on the response to serotonin. These data indicate that serotonin has a postsynaptic inhibitory action by an activating potassium conductance. The possibility of a regulation of calcium currents is discussed. The possible role of serotonin on intrinsic synaptic transmission is also discussed.

Action Potentials↗

Differential effects of a benzodiazepine on synaptic transmissions in rat hippocampal neurons in vitro.

The effects of midazolam, one of the most popular benzodiazepines, on synaptic transmissions were compared with intracellular recordings between CA1 pyramidal cells (CA1-PCs) and dentate gyrus granule cells (DG-GCs) in rat hippocampal slices. First, we studied the effects of midazolam on orthodromically evoked spikes, membrane properties and synaptic potentials. Secondly, the effects of a GABA(A) receptor agonist, muscimol, were examined on membrane properties to determine whether or not the densities of GABA(A) receptors are different between CA1-PCs and DG-GCs. Midazolam (75 microM) markedly depressed orthodromically evoked spikes in CA1-PCs, compared with those in DG-GCs. A GABA(A) receptor antagonist, bicuculline (10 microM), almost completely antagonized the depressant effects of midazolam on spike generation in CA1-PCs, whereas it had little effect on midazolam in dentate gyrus granule cells. Midazolam produced either depolarizing or hyperpolarizing effects on resting membrane potentials (Vm) with an input resistance decrease in CA1-PCs, whereas it produced depolarized Vm in DG-GCs. Midazolam significantly increased the amplitude of monosynaptic inhibitory postsynaptic potentials in CA1-PCs, whereas midazolam slightly decreased these in DG-GCs. Midazolam significantly decreased the amplitude of excitatory postsynaptic potentials both in CA1-PCs and DG-GCs. Muscimol (100 microM) produced either depolarizing or hyperpolarizing effects on Vm with an input resistance decrease in CA1-PCs, and it depolarized Vm with an input resistance decrease in DG-GCs. These results demonstrate that midazolam has differential effects on excitatory and inhibitory synaptic transmissions in hippocampal neurons. The mechanism of this difference could be partly due to the different types of GABA(A) receptors between CA1-PCs and DG-GCs.

2-Amino-5-phosphonovalerate↗