Recurrent Collaterals Research Articles

Neurokinin-receptor-mediated depolarization of cortical neurons elicits an increase in glutamate release at excitatory synapses.

Using whole-cell patch-clamp recordings of spontaneous synaptic activity, we have previously shown that activation of neurokinin-1 (NK1) but not NK3 receptors leads to increased GABA release onto principal cells in the rat entorhinal cortex. In the present study, we examine the effect of activation of these receptors on spontaneous excitatory synaptic responses mediated by glutamate. Both neurokinin B (NKB) and the specific NK3 receptor agonist, senktide, increased the spontaneous release of glutamate, and a similar effect was also seen with substance P (SP) and other NK1 receptor agonists. The increased release induced by either SP or senktide was absent in the presence of tetrodotoxin, demonstrating that it was likely to occur via activation of presynaptic excitatory neurons. Current-clamp recordings confirmed that principal neurons were depolarized by both NK3 and NK1 agonists. However, the response to the former but not the latter persisted in tetrodotoxin, allowing us to conclude that NK3 receptor activation provoked glutamate release via recurrent collaterals between principal neurons, whereas the NK1 receptors may be localized to excitatory interneurons. Finally, the increased release induced by senktide, but not SP, was reduced by an antagonist of group III metabotropic glutamate receptors. Thus, glutamate release from recurrent collaterals is facilitated by a presynaptic group III autoreceptor [Evans, D.I.P., Jones, R.S.G. & Woodhall, G.L. (2000) J. Neurophysiol.,83, 2519-2525], whereas the terminals of neurons responsible for the NK1-receptor induced glutamate release may not bear these receptors. These results have implications for control of activity and epileptogenesis in cortical networks.

Extending the cerebellar Lugaro cell class

We describe here, in Golgi-impregnated rat cerebellar cortex, a new group of large granular layer neurons. These cells have a globular soma located at variable depths in the granular layer, and three to four long radiating dendrites coursing through the three layers of the cortex. The axon projects more or less directly into the molecular layer, where it expands in a local plexus of oblique and tortuous thick collaterals ascending through the major part of the layer. Interestingly, the axons of several of these cells give off a collateral that courses for a long distance in the transverse direction, just above the Purkinje cell somata, parallel to the parallel fibers. While the granular layer location and the polymorphous somato-dendritic pattern of these cells is reminiscent of that of Golgi cells, their axonal pattern is clearly of the same type as that of another large granular layer interneuron, the Lugaro cell. Moreover, double anti-calretinin and anti-calbindin immunolabellings show that Lugaro cells as well as some globular somata dispersed in the granular layer are both calretinin-positive and in close apposition with numerous calbindin-positive varicosities of Purkinje cell axon recurrent collaterals. These latter are known from previous ultrastructural studies to be pre-synaptic to Lugaro cells. The common granular layer location and calretinin labelling, the striking similarity in axonal projection pattern, and the important common recurrent afferentation by Purkinje cell axons strongly argue in favor of the classification of these globular interneurons as a subgroup of a widened Lugaro cell type.

Selective GABAergic innervation of thalamic nuclei from zona incerta.

Thalamocortical circuits that govern cortical rhythms and ultimately effect sensory transmission consist of three major interconnected elements: excitatory thalamocortical and corticothalamic neurons and GABAergic cells in the reticular thalamic nucleus. Based on the present results, a fourth component has to be added to this scheme. GABAergic fibres from an extrareticular diencephalic source were found to selectively innervate relay cells located mainly in higher-order thalamic nuclei. The origin of this pathway was localized to zona incerta (ZI), known to receive collaterals from corticothalamic fibres. First-order nuclei were innervated only in zones showing a high density of calbindin-positive neurons. The large GABA-immunoreactive incertal terminals established multiple contacts preferentially on the proximal dendrites of relay cells via symmetrical synapses with multiple release sites. The distribution, ultrastructural characteristics and postsynaptic target selection of extrareticular terminals were similar to type II muscarinic acetylcholine receptor-positive boutons, which constituted up to 49% of all GABAergic terminals in the posterior nucleus. This suggests that a significant proportion of the GABAergic input into certain thalamic territories involved in higher-order functions may have extrareticular origin. Unlike the reticular nucleus, ZI receives peripheral and layer V cortical input but no thalamic feedback; it projects to brainstem centres and has extensive intranuclear recurrent collaterals. This indicates that ZI exerts a conceptually new type of inhibitory control over the thalamus. The proximally situated, multiple active zones of ZI terminals indicate a powerful influence on the firing properties of thalamic neurons, which is conveyed to multiple cortical areas via relay cells which have widespread projections to neocortex.

Statistical model relating CA3 burst probability to recovery from burst-induced depression at recurrent collateral synapses.

When neuronal excitability is increased in area CA3 of the hippocampus in vitro, the pyramidal cells generate periodic bursts of action potentials that are synchronized across the network. We have previously provided evidence that synaptic depression at the excitatory recurrent collateral synapses in the CA3 network terminates each population burst so that the next burst cannot begin until these synapses have recovered. These findings raise the possibility that burst timing can be described in terms of the probability of recovery of this population of synapses. Here we demonstrate that when neuronal excitability is changed in the CA3 network, the mean and variance of the interburst interval change in a manner that is consistent with a timing mechanism comprised of a pool of exponentially relaxing pacemakers. The relaxation time constant of these pacemakers is the same as the time constant describing the recovery from activity-dependent depression of recurrent collateral synapses. Recovery was estimated from the rate of spontaneous transmitter release versus time elapsed since the last CA3 burst. Pharmacological and long-term alterations of synaptic strength and network excitability affected CA3 burst timing as predicted by the cumulative binomial distribution if the burst pace-maker consists of a pool of recovering recurrent synapses. These findings indicate that the recovery of a pool of synapses from burst-induced depression is a sufficient explanation for burst timing in the in vitro CA3 neuronal network. These findings also demonstrate how information regarding the nature of a pacemaker can be derived from the temporal pattern of synchronous network activity. This information could also be extracted from less accessible networks such as those generating interictal epileptiform discharges in vivo.

Interactions between cerebellar Purkinje cells and their associated astrocytes.

Some neurons, including cerebellar Purkinje cells, are completely ensheathed by astrocytes. When granule cell neurons and functional glia were eliminated from newborn mouse cerebellar cultures by initial exposure to a DNA synthesis inhibitor, Purkinje cells lacked glial sheaths and there was a tremendous sprouting of Purkinje cell recurrent axon collaterals, terminals of which hyperinnervated Purkinje cell somata, including persistent somatic spines, and formed heterotypical synapses with Purkinje cell dendritic spines, sites usually occupied by parallel fiber (granule cell axon) terminals. Purkinje cells in such preparations failed to develop complex spikes when recorded from intracellularly, and their membrane input resistances were low, making them less sensitive to inhibitory input. If granule cells and oligodendrocytes were eliminated, but astrocytes were not compromised, sprouting of recurrent axon collaterals occurred and their terminals projected to Purkinje cell dendritic spines, but the Purkinje cells had astrocytic sheaths, their somata were not hyperinnervated, the somatic spines had disappeared, complex spike discharges predominated, and membrane input resistance was like that of Purkinje cells in untreated control cultures. When cerebellar cultures without granule cells and glia were transplanted with granule cells and/or glia from another source, a series of changes occurred that included stripping of excess Purkinje cell axosomatic synapses by astrocytic processes, reduction of heterotypical axospinous synapses in the presence of astrocytes, disappearance of Purkinje cell somatic spines with astrocytic ensheathment, and proliferation of Purkinje cell dendritic spines after the introduction of astrocytes. Dendritic spine proliferation was followed by formation of homotypical axospinous synapses when granule cells were present or persistence as unattached spines in the absence of granule cells. The results of these studies indicate that astrocytes regulate the numbers of Purkinje cell axosomatic and axospinous synapses, induce Purkinje cell dendritic spine proliferation, and promote the structural and functional maturation of Purkinje cells.

Selective inhibition of local excitatory synaptic transmission by serotonin through an unconventional receptor in the CA1 region of rat hippocampus.

1. The modulation of synaptic transmission by serotonin (5-HT) was studied using whole-cell voltage-clamp and sharp-electrode current-clamp recordings from CA1 pyramidal neurones in transverse rat hippocampal slices in vitro. 2. With GABA(A) receptors blocked, polysynaptic transmission evoked by stratum radiatum stimulation was inhibited by submicromolar concentrations of 5-HT, while monosynaptic excitatory transmission and CA1 pyramidal neurone excitability were unaffected. The effect persisted following pharmacological blockade of 5-HT(1A) and 5-HT(4) receptors, which directly affect CA1 pyramidal neurone excitability. 3. Concentration-response relationships for 5-HT were determined in individual neurones; the EC(50) values for block of polysynaptic excitation and inhibition by 5-HT were approximately 230 and approximately 160 nM, respectively. The 5-HT receptor type responsible for the observed effect does not fall easily into the present classification of 5-HT receptors. 4. 5-HT inhibition of polysynaptic EPSCs persisted following complete block of GABAergic transmission and in CA1 minislices, ruling out indirect effects through interneurones and non-CA1 pyramidal neurones, respectively. 5. Monosynaptic EPSCs evoked by stimulation of CA1 afferent pathways appeared to be unaffected by 5-HT. Monosynaptic EPSCs evoked by stimulation of the alveus, which contains CA1 pyramidal neurone axons, were partially inhibited by 5-HT. 6. We conclude that 5-HT inhibited synaptic transmission by acting at local recurrent collaterals of CA1 pyramidal neurones. This may represent an important physiological action of 5-HT in the hippocampus, since it occurs over a lower concentration range than the 5-HT effects reported so far.

The Involvement of Recurrent Connections in Area CA3 in Establishing the Properties of Place Fields: a Model

Strong constraints on the neural mechanisms underlying the formation of place fields in the rodent hippocampus come from the systematic changes in spatial activity patterns that are consequent on systematic environmental manipulations. We describe an attractor network model of area CA3 in which local, recurrent, excitatory, and inhibitory interactions generate appropriate place cell representations from location- and direction-specific activity in the entorhinal cortex. In the model, familiarity with the environment, as reflected by activity in neuromodulatory systems, influences the efficacy and plasticity of the recurrent and feedforward inputs to CA3. In unfamiliar, novel, environments, mossy fiber inputs impose activity patterns on CA3, and the recurrent collaterals and the perforant path inputs are subject to graded Hebbian plasticity. This sculpts CA3 attractors and associates them with activity patterns in the entorhinal cortex. In familiar environments, place fields are controlled by the way that perforant path inputs select among the attractors. Depending on the training experience provided, the model generates place fields that are either directional or nondirectional and whose changes when the environment undergoes simple geometric transformations are in accordance with experimental data. Representations of multiple environments can be stored and recalled with little interference, and these have the appropriate degrees of similarity in visually similar environments.

Recurrent mossy fibers preferentially innervate parvalbumin-immunoreactive interneurons in the granule cell layer of the rat dentate gyrus.

Detection of vesicular zinc and immunohistochemistry against markers for different interneuron subsets were combined to study the postsynaptic target selection of zinc-containing recurrent mossy fiber collaterals in the dentate gyrus. Mossy fiber collaterals in the granule cell layer selectively innervated parvalbumin-containing cells, with numerous contacts per cell, whereas the granule cells were avoided. Under the electron microscope, those boutons made asymmetrical contacts on dendrites and somata. These findings suggest that, in addition to the hilar perforant path-associated (HIPP) interneurons, the basket and chandelier cells also receive a powerful feed-back drive from the granule cells, and thereby are able to control population synchrony in the dentate gyrus. On the other hand, the amount of monosynaptic excitatory feed-back among granule cells is shown to be negligible.

Circuit mechanisms of spike-wave discharge: are there similar underpinnings for centrotemporal spikes?

Comparisons of Generalized Absence and Benign Focal Epilepsies In the context of exploring the underlying circuit pathology of benign focal epilepsy (BFE) it is perhaps useful to consider similarities to generalized absences (GA), about which we have learned a great deal from animal models in recent years. Although there are clear differences in the clinical presentation of the two syndromes, especially the focal nature of BFE compared to the widely generalized activity of GA, similarities include some EEG findings and pharmacology. On the EEG, a variable fraction of BFE patients will exhibit diffuse spike and wave discharge, these can be modulated by arousal level, and often occur during sleep. This EEG finding, which is typical of GA, is sometimes seen in additional to the Rolandic sharp waves that are characteristic of BFE. This suggests that similar, but not completely overlapping, circuits may be involved in the genesis of such activity. Similarities in pharmacology support this idea. For example, carbamazepine may exacerbate both GA and BFE. Vigabatrin, which enhances inhibitory responses in the brain, and can promote GA activity, has been reported to increase EEG abnormalities in BFE. In the following section, we will summarize the proposed inhibitory mechanisms of GA, and speculate how similar mechanisms may be invoked in rolandic spike activity. Thalamocortical Circuitry of Generalized Absence Epilepsy An integrated, recurrent synaptic loop that tightly binds thalamic and cortical circuits, and mediates sensory perception and modulation of arousal, has been described (Steriade and Llinas, 1988). Briefly, this circuit is composed of interconnected regions in dorsal thalamus, thalamic reticular nucleus (TRN), and cortex. Normally, sensory information is relayed through dorsal thalamus to the appropriate cortical region. Thalamocortical fibers traverse the TRN and emit recurrent excitatory collaterals that mediate activation of TRN neurons. The TRN cells, which are uniformly GABAergic, provide a powerful and widespread feedback inhibition onto dorsal thalamus (Huguenard and Prince, 1994a;Cox et al., 1996). Synaptic inhibition of dorsal thalamic neurons can lead to rebound activation, which has the potential to initiate reverberant activity in this circuit (Steriade et al., 1993;Huguenard and Prince, 1994a). It is proposed that divergence within this system may allow for the generalization of spike wave discharge in GA. For example, some TRN cells can project to widespread regions of dorsal thalamus in rat (Cox et al., 1996) and mouse (Scheibel and Scheibel, 1966). Exacerbation of GA by pro-GABAergic drugs is consistent with a strong inhibitory component to these seizures. Hypersynchronous thalamocortical activity in mouse mutants: implications for pathogenesis An important synaptic element in the thalamocortical circuit is a demonstrated reciprocal connectivity between TRN cells (Scheibel and Scheibel, 1966;Steriade and Deschenes, 1984;Ulrich and Huguenard, 1995). It has been proposed that this can either promote or desynchronize thalamocortical oscillations (Steriade et al., 1993). In a recent study (Huntsman et al., 1999), we have shown that mutant mice that were devoid of a particular GABAA subunit (β3) lacked functional connectivity between TRN cells. These mice had absence seizures and a very high degree of widespread hypersynchrony in isolated thalamic slices. These findings suggest that the reciprocal interconnections between TRN cells normally serve to desynchronize thalamocortical activity and prevent widespread, i.e. generalized, activity. Further, the view that the TRN network itself drives the generation of GA is not supported. These results are consistent with reports in ferret (von Krosigk et al., 1993) and rat (Huguenard and Prince, 1994b) thalamic slices, where pharmacological upor downregulation of intra-RTN inhibition can suppress or promote intrathalamic epileptiform activity, respectively.

Mossy fiber zinc and temporal lobe epilepsy: pathological association with altered "epileptic" gamma-aminobutyric acid A receptors in dentate granule cells.

Temporal lobe epilepsy is associated with circuit rearrangements within the hippocampus. Mossy fibers sprout and pathologically innervate the inner molecular layer of the dentate gyrus, providing a recurrent excitatory pathway not present in the control brain. In addition to releasing glutamate, these recurrent collaterals also release zinc, which can accumulate in high concentrations in the extracellular space. Accompanying these dentate gyrus circuit rearrangements are alterations in the subunit expression patterns and pharmacology of gamma-aminobutyric acid A (GABAA) receptors in dentate granule cells. In normal, control granule cells, GABAA receptors are zinc insensitive as a result of high levels of expression of the alpha1 subunit in these cells. In epileptic brain, expression of alpha1 subunits decreases and expression of alpha4 and delta subunits increases, leading to the assembly of GABAA receptors that are exquisitely zinc sensitive. This temporal and spatial association of the expression of zinc-sensitive GABAA receptors and the emergence of a zinc-delivery system unique to the epileptic hippocampus has led to the formulation of an hypothesis that suggests that zinc release during repetitive activation of the dentate gyrus may lead to a catastrophic failure of inhibition under conditions mediating seizure initiation. This could contribute to the limbic hyperexcitability characteristic of temporal lobe epilepsy.

Reversible Inactivation of the Hippocampal Mossy Fiber Synapses in Mice Impairs Spatial Learning, but neither Consolidation nor Memory Retrieval, in the Morris Navigation Task

The role played by hippocampal mossy fibers in the learning and memory processes implemented in the Morris swimming navigation task has been studied in C57BL/6 mice by selective and reversible inactivation of mossy fiber synaptic fields by diethyldithiocarbamate. The functional integrity of the mossy fibers proved essential for the storage of the spatial representation on the modifiable synapses of the recurrent collaterals of the CA3 pyramidal cells, whereas it is not necessary for the consolidation and recall of spatial memories. The results suggest that mossy fibers are preferentially involved in new learning. They are consistent with the hypothesis that the hippocampal CA3 region might act as an autoassociation memory.

Sensorimotor Integration at the Dorsal Column Nuclei.

Interaction among primary afferents, corticofugal fibers, and intrinsic elements allows for sensorimotor integration at the dorsal column nuclei. The interneurons permit the spatial localization, the recurrent collaterals synchronize the activity of projecting cells with overlapping receptive fields, and the corticofugal fibers induce a central zone of activity surrounded by a peripheral zone of inhibition.

Reflex pathways from large muscle spindle afferents and recurrent axon collaterals to motoneurones of wrist and digit muscles: a comparison in cats, monkeys and humans.

Whereas a large body of data is available on the control of hand motoneurones from the brain, not much is known about the contribution of the spinal interneuronal apparatus to the differentiated movement repertoire of the hand. This review summarises recent data on the excitatory Ia pathways and on recurrent inhibition for cats, monkeys and humans. The basic principles of organisation have, in general, been preserved in the different species. Thus the motoneurones to cat and human long and short digit muscles seem not to possess a recurrent axon collateral system. With regard to the Ia pathways, specialised connectivity patterns have developed in the long digit extensor and wrist extensor muscles. They allow the former group to support the differentiated movement repertoire of the digits, and the latter group to be part of a general extensor or flexor synergism. Modifications between the species are present, however, with regard to the proximodistal connectivity across the elbow. Whereas they are regularly present in the cat, they are less developed in the monkey and absent in man, which frees the human hand from the elbow position.

Identification of an Interneuronal Population that Mediates Recurrent Inhibition of Motoneurons in the Developing Chick Spinal Cord

Studies on the development of synaptic specificity, embryonic activity, and neuronal specification in the spinal cord have all been limited by the absence of a functionally identified interneuron class (defined by its unique set of connections). Here, we identify an interneuron population in the embryonic chick spinal cord that appears to be the avian equivalent of the mammalian Renshaw cell (R-interneurons). These cells receive monosynaptic nicotinic, cholinergic input from motoneuron recurrent collaterals. They make predominately GABAergic connections back onto motoneurons and to other R-interneurons but project rarely to other spinal interneurons. The similarity between the connections of the developing R-interneuron, shortly after circuit formation, and the mature mammalian Renshaw cell raises the possibility that R-interneuronal connections are formed precisely from the onset. Using a newly developed optical approach, we identified the location of R-interneurons in a column, dorsomedial to the motor nucleus. Functional characterization of the R-interneuron population provides the basis for analyses that have so far only been possible for motoneurons.

The effects of median raphé electrical stimulation on serotonin release in the dorsal hippocampal formation of prenatally protein malnourished rats

Our previous work had shown an enhanced inhibition in the hippocampal formation of prenatally protein malnourished rats. We have also found a diminishment in 5-hydroxytryptamine (5-HT) fibers in the hippocampal formation of malnourished rats as well as increased levels of 5-HT in the brain. The purpose of the present study was to determine 5-HT release in the dorsal hippocampal formation following electrical stimulation of the median raphé nucleus (MRN) in unanesthetized prenatally malnourished rats. Stimulation of this nucleus at 20 Hz in malnourished rats resulted in a significantly diminished release of 5-HT compared to well-nourished rats. The latter group showed a lesser, though still significant, decrease in 5-HT release following raphé stimulation. Basal release of 5-HT prior to stimulation was significantly higher in malnourished rats as compared to well-nourished controls. This may be the result of a decreased density of 5-HT neurons leading to a diminished control of release. Stimulation of the MRN in behaving malnourished animals may markedly affect the recurrent negative feedback collaterals onto somatodendritic 5-HT 1A and 5-HT 1D autoreceptors thus enhancing the inhibitory effects of stimulation of the median raphé on 5-HT release. Studies are underway to examine the sensitivity of both the somatodendritic and terminal 5-HT autoreceptors in malnourished animals, in order to understand possible mechanisms for our findings.

Glutamate Receptors Mediate TTX-Resistant Synchronous Activity in the Rat Hippocampus

4-Aminopyridine (4-AP) is a well known convulsant that enhances the release of both excitatory and inhibitory neurotransmitters in the CNS. Low concentrations of 4-AP (approximately 100 microM) readily induce synchronized discharges in the hippocampus that are blocked by tetrodotoxin (TTX), suggesting that they require Na(+)-dependent action potentials in addition to the enhanced release of neurotransmitters. However, in the present study we have found that higher concentrations of 4-AP (1 mM) in combination with 5 mM tetraethylammonium (TEA) induce spontaneous synchronized discharges in rat hippocampal slices that are resistant to blockade by TTX. These synchronous discharges are evident in field potential recordings, which progress from the hilus to CA1 at 0.023 +/- 0.002 m/sec and in intracellular recordings from the hilar mossy cells and CA3 pyramidal cells. In some slices exposed to 4-AP and TEA, smaller-amplitude asynchronous responses also were recorded. 4-AP-induced spontaneous discharges are blocked by 20 microM DNQX and by 100 microM Cd(2+) but are resistant to blockade by either 25 microM bicuculline or 25 microM D-APV. These results suggest that the activation of postsynaptic AMPA receptors is necessary to produce TTX-resistant synchronized discharges. The laminar profile of field potentials recorded in CA3 and CA1 suggests that glutamate is released from axons of CA3 pyramidal cells despite the blockade of fast axonal Na(+) channels by TTX. Synchronous discharges may result from glutamate released at proximal recurrent collaterals after spontaneous Ca(2+) spikes in CA3 pyramidal cells.

Glutamate controls the induction of GABA-mediated giant depolarizing potentials through AMPA receptors in neonatal rat hippocampal slices.

Glutamate controls the induction of GABA-mediated giant depolarizing potentials through AMPA receptors in neonatal rat hippocampal slices. Giant depolarizing potentials (GDPs) are generated by the interplay of the depolarizing action of GABA and glutamate. In this study, single and dual whole cell recordings (in current-clamp configuration) were performed from CA3 pyramidal cells in hippocampal slices obtained from postnatal (P) days P1- to P6-old rats to evaluate the role of ionotropic glutamate receptors in GDP generation. Superfusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10-40 microM) completely blocked GDPs. However, in the presence of CNQX, it was still possible to re-induce the appearance of GDPs with GABA (20 microM) or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxadepropionate (AMPA) (5 microM). This effect was prevented by the more potent and selective AMPA receptor antagonist GYKI 53655 (50-100 microM). In the presence of GYKI 53655, both kainic or domoic acid (0.1-1 microM) were unable to induce GDPs. In contrast, bath application of D-(-)-2-amino-5-phosphonopentanoic acid (50 microM) or (+)-3-(2carboxy-piperazin-4-yl)-propyl-L-phosphonic acid (20 microM) produced only a 37 +/- 9% (SE) and 36 +/- 11% reduction in GDPs frequency, respectively. Cyclothiazide, a selective blocker of AMPA receptor desensitization, increased GDP frequency by 76 +/- 14%. Experiments were also performed with an intracellular solution containing KF to block GABAA receptor-mediated responses. In these conditions, a glutamatergic component of GDP was revealed. GDPs could still be recorded synchronous with those detected simultaneously with KCl-filled electrodes, although their amplitude was smaller. Similar results were found in pair recordings obtained from minislices containing only a small portion of the CA3 area. These data suggest that GDP generation requires activation of AMPA receptors by local release of glutamate from recurrent collaterals.

Activity Patterns and Synaptic Organization of Ventrally Located Interneurons in the Embryonic Chick Spinal Cord

To investigate the origin of spontaneous activity in developing spinal networks, we examined the activity patterns and synaptic organization of ventrally located lumbosacral interneurons, including those whose axons project into the ventrolateral funiculus (VLF), in embryonic day 9 (E9)-E12 chick embryos. During spontaneous episodes, rhythmic synaptic potentials were recorded from the VLF and from spinal interneurons that were synchronized, cycle by cycle, with rhythmic ventral root potentials. At the beginning of an episode, ventral root potentials started before the VLF discharge and the firing of individual interneurons. However, pharmacological blockade of recurrent motoneuron collaterals did not prevent or substantially delay interneuron recruitment during spontaneous episodes. The synaptic connections of interneurons were examined by stimulating the VLF and recording the potentials evoked in the ventral roots, in the VLF, or in individual interneurons. Low-intensity stimulation of the VLF evoked a short-latency depolarizing potential in the ventral roots, or in interneurons, that was probably mediated mono- or disynaptically. At higher intensities, long-latency responses were recruited in a highly nonlinear manner, eventually culminating in the activation of an episode. VLF-evoked potentials were reversibly blocked by extracellular Co2+, indicating that they were mediated by chemical synaptic transmission. Collectively, these findings indicate that ventral interneurons are rhythmically active, project to motoneurons, and are likely to be interconnected by recurrent excitatory synaptic connections. This pattern of organization may explain the synchronous activation of spinal neurons and the regenerative activation of spinal networks when provided with a suprathreshold stimulus.

Analysis of information transmission in the Schaffer collaterals.

Hippocampal region CA1 seems from comparative studies to be particularly important in the primate brain, in addition to being crucial to memory function. Thus, it is an extremely appropriate place to begin a quantitative investigation of the information representation and transmission capabilities of cerebral neural networks. In this study, a mathematical model of the Schaffer collateral projection from CA3 to CA1 is described. From the model, the amount of information that can be conveyed by the Schaffer collaterals is calculated, i.e., the information that a pattern of firing in CA1 conveys about a pattern of firing in CA3, because of the connections between them. The calculation is performed analytically for an arbitrary probability distribution describing the pattern of CA3 firing and then solved numerically for particular input distributions. The effect of a number of issues on the information conveyed is examined. Consideration of the effect of the amount of analog resolution of firing rates in the patterns of activity in CA3 confirmed information transmission to be most efficient for binary codes, to a degree that depends on the sparseness of activity. For very sparse codes, a binary code allows more information to be received even in absolute terms, but for more distributed codes, slightly more information can be received by CA1 by making use of analog resolution. The pattern of convergence of connections from CA3 to CA1 is examined, i.e., the spatial distribution of the number of connections each CA1 neuron receives. It is found that the effect of the difference between a uniform convergence model and a proposed real convergence pattern (Bernard and Wheal, Hippocampus 1994;4:497-529) is minimal. The effect of the ratio of expansion between CA3 and CA1 due to the relative numbers of neurons in these two areas is studied. The Schaffer collaterals in all mammalian species reported in the literature seem to operate in a regime in which there is at least the scope for efficient transfer of information. In addition, the effect of topography (with respect to the transverse hippocampal axis) in the Schaffer collateral connectivity is examined. In the absence of spatial correlations, topography is found to have essentially no effect on information transmission. If spatial correlations in firing were present in CA3 (which, however, would be less efficient for memory storage in the recurrent collaterals), information transmission would be maximized by matching the topographic spread to the spatial scale of correlation.

Chapter 18 P2 receptor-mediated activation of noradrenergic and dopaminergic neurons in the rat brain

Publisher Summary Focal electrical stimulation evokes in the rat locus coeruleus (LC) biphasic synaptic potentials consisting of early depolarizing (p.s.p.) and late hyperpolarizing (i.p.s.p.) components. It has been found that the p.s.p. is because of the release of glutamate from afferent fibres predominantly onto non-N-methyl-D- aspartate (non-NMDA) receptors and of γ-aminobutyric acid (GABA) onto GABAA receptors. In the chapter, the investigations demonstrate the presence of release stimulatory P2 receptors in the central noradrenergic and dopaminergic systems. Hence, exogenously applied or endogenously released ATP may excite noradrenergic neurons of the LC and dopaminergic neurons of the ventral tegmental area (VTA). ATP and its structural analog 2-MeSATP depolarized LC neurons in a slice preparation. In addition, there is strong evidence for the contribution of ATP to excitatory synaptic potentials recorded from the neurons themselves; this ATP appears to be coreleased with noradrenaline from recurrent axon collaterals or dendrites. A combined methodological approach was used to prove the presence of P2 receptors in the VTA and its main projection target in the NAc. Although electrophysiological recordings from VTA neurons in a slice preparation failed to show a depolarizing response to 2-MeSATP, the application of 2-MeSATP into the VTA via a microdialysis probe was a powerful stimulus of dopamine release in vivo.