Fig 9 - uploaded by Luis M. Franco
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Confocal images of the mossy fibers and the Schaffer collaterals. The MFs run through a narrow layer (stratum lucidum), where they contact the proximal third of the apical dendrite of the pyramidal cells. Notice the giant boutons and boutons en passant from which filopodial extensions originate. In contrast, the SCs run through the stratum radiatum of CA1 innervating a broader area of the dendritic tree of pyramidal cells. Anatomical and myelination differences, as well as high density of Na+ channels in the MFs could account for the frequency potentiation of the antidromic responses of this pathway.
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To better understand information transfer along the hippocampal pathways and its plasticity, here we studied the antidromic responses of the dentate gyrus (DG) and CA3 to activation of the mossy fibers and Schaffer collaterals, respectively, in hippocampal slices from naïve and epileptic rats. We applied trains of 600 electrical stimuli at function...
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... The characteristic values of APS potential waveforms have been used to evaluate the synchronous firing of a population of neurons, such as area and amplitude of APS representing the number of firing neurons (Andersen et al., 1971;Richardson et al., 1987;Varona et al., 2000;Franco et al., 2016). Here the amplitude, area, and latency of the APS waveform were calculated to evaluate the differences in neuronal firing induced by different types of pulses ( Figure 1B). ...
Electrical pulses have been promisingly utilized in neural stimulations to treat various diseases. Usually, charge-balanced biphasic pulses are applied in the clinic to eliminate the possible side effects caused by charge accumulations. Because of its reversal action to the preceding cathodic phase, the subsequent anodic phase has been commonly considered to lower the activation efficiency of biphasic pulses. However, an anodic pulse itself can also activate axons with its “virtual cathode” effect. Therefore, we hypothesized that the anodic phase of a biphasic pulse could facilitate neuronal activation in some circumstances. To verify the hypothesis, we compared the activation efficiencies of cathodic pulse, biphasic pulse, and anodic pulse applied in both monopolar and bipolar modes in the axonal stimulation of alveus in rat hippocampal CA1 region in vivo. The antidromically evoked population spikes (APS) were recorded and used to evaluate the amount of integrated firing of pyramidal neurons induced by pulse stimulations. We also used a computational model to investigate the pulse effects on axons at various distances from the stimulation electrode. The experimental results showed that, with a small pulse intensity, a cathodic pulse recruited more neurons to fire than a biphasic pulse. However, the situation was reversed with an increased pulse intensity. In addition, setting an inter-phase gap of 100 μs was able to increase the activation efficiency of a biphasic pulse to exceed a cathodic pulse even with a relatively small pulse intensity. Furthermore, the latency of APS evoked by a cathodic pulse was always longer than that of APS evoked by a biphasic pulse, indicating different initial sites of the neuronal firing evoked by the different types of pulses. The computational results of axon modeling showed that the subsequent anodic phase was able to relieve the hyperpolarization block in the flanking regions generated by the preceding cathodic phase, thereby increasing rather than decreasing the activation efficiency of a biphasic pulse with a relatively great intensity. These results of both rat experiments and computational modeling firstly reveal a facilitation rather than an attenuation effect of the anodic phase on biphasic-pulse stimulations, which provides important information for designing electrical stimulations for neural therapies.
... Stimulating axons in the alveus regularly elicited a field response in the pyramidal layer of CA1. This field response had a characteristic negative component (Fig. 1b), representing multiple synchronous antidromic action potentials (Franco et al. 2015). The following positive component (Fig. 1b, left) arises due to recurrent synaptic excitation within CA1. ...
Axonal excitability is an important determinant for the accuracy, direction and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (INaP). Recent evidence indicates that action potentials can also be generated at remote locations along the axonal fiber, giving rise to ectopic action potentials (eAP) during physiological states (e.g., fast network oscillations) or in pathological situations (e.g., following demyelination). Here, we investigated how ectopic axonal excitability of mouse hippocampal CA1 pyramidal neurons is regulated by INaP. Recordings of field potentials and intracellular voltage in brain slices revealed that electrically evoked antidromic spikes were readily suppressed by two different blockers of INaP, riluzole and phenytoin. The effect was mediated by a reduction of the probability of ectopic spike generation while latency was unaffected. Interestingly, the contribution of INaP to excitability was much more pronounced in axonal branches heading towards the entorhinal cortex compared to the opposite fiber direction towards fimbria. Thus, excitability of distal CA1 pyramidal cell axons is affected by persistent sodium currents in a direction‐selective manner. This mechanism may be of importance for ectopic spike generation in oscillating network states as well as in pathological situations.
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... Moreover, they showed that these receptors coexist with glutamate receptors in the post-synaptic site. GABA acting on GABA A receptors modulates the excitability of the MFs Treviñ o and Gutié rrez, 2005;Franco et al., 2015) and therefore further release of neurotransmitter (Treviñ o and Gutié rrez, 2005;Yamamoto et al., 2011). On the other hand, it is well known that GABA B receptors are present in the MF terminals and their activation with the agonist baclophen inhibits the release of GABA from the MFs (Gutié rrez, 2002). ...
... Granule cells from control rats express VGlut but not VGAT, while GCs from epileptic rats (C 2 ) express both VGlut and VGAT mRNAs. the MFs acts to regulate further release of neurotransmitter and modulates information transfer of the MFs by acting on GABA A Treviñ o and Gutié rrez, 2005;Franco et al., 2015;Yamamoto et al., 2011), as well as on GABA B receptors (Gutié rrez, 2002;Safiulina and Cherubini, 2009;Cabezas et al., 2012;Valente et al., 2015). ...
... We explored whether the preference to fire at a given frequency depended on the transmission of information of the MFs or on the proneness of the pyramidal cells to follow such a frequency. We found that it was the axon (MF) conduction properties that were involved in this phenomenon and revealed a resonance phenomenon of axonal action potential conduction, which was strongly affected by activation of presynaptic and axonal ionotropic glutamate and GABA A receptors (Franco et al., 2015). ...
(2016) Journal of Chemical Neuroanatomy - Vol.73:1-42
... Granule cells from control rats express VGlut but not VGAT, while GCs from epileptic rats (C 2 ) express both VGlut and VGAT mRNAs. the MFs acts to regulate further release of neurotransmitter and modulates information transfer of the MFs by acting on GABA A Treviñ o and Gutié rrez, 2005;Franco et al., 2015;Yamamoto et al., 2011), as well as on GABA B receptors (Gutié rrez, 2002;Safiulina and Cherubini, 2009;Cabezas et al., 2012;Valente et al., 2015). ...
... We explored whether the preference to fire at a given frequency depended on the transmission of information of the MFs or on the proneness of the pyramidal cells to follow such a frequency. We found that it was the axon (MF) conduction properties that were involved in this phenomenon and revealed a resonance phenomenon of axonal action potential conduction, which was strongly affected by activation of presynaptic and axonal ionotropic glutamate and GABA A receptors (Franco et al., 2015). ...
... Moreover, they showed that these receptors coexist with glutamate receptors in the post-synaptic site. GABA acting on GABA A receptors modulates the excitability of the MFsTreviñ o and Gutié rrez, 2005;Franco et al., 2015) and therefore further release of neurotransmitter(Treviñ o and Gutié rrez, 2005;Yamamoto et al., 2011). On the other hand, it is well known that GABA B receptors are present in the MF terminals and their activation with the agonist baclophen inhibits the release of GABA from the MFs(Gutié rrez, 2002). ...
The granule cells (GCs) and their axons, the mossy fibers (MFs), make synapses with interneurons in the hilus and CA3 area of the hippocampus and with pyramidal cells of CA3, each with distinct anatomical and functional characteristics. Many features of synaptic communication observed at the MF synapses are not usually observed in most cortical synapses, and thus have drawn the attention of many groups studying different aspects of the transmission of information. One particular aspect of the GCs, that makes their study unique, is that they express a dual glutamatergic-GABAergic phenotype and several groups have contributed to the understanding of how two neurotransmitters of opposing actions can act on a single target when simultaneously released. Indeed, the GCs somata and their mossy fibers express in a regulated manner glutamate and GABA, GAD, VGlut and VGAT, all markers of both phenotypes. Finally, their activation provokes both glutamate-R-mediated and GABA-R-mediated synaptic responses in the postsynaptic cell targets and even in the MFs themselves. The developmental and activity-dependent expression of these phenotypes seem to follow a "logical" way to maintain an excitation-inhibition balance of the dentate gyrus-to - CA3 communication.
Fast ripples (FRs; activity of >250 Hz) have been considered as a biomarker of epileptic activity in the hippocampus and entorhinal cortex; it is thought that they signal the focus of seizure generation. Similar high-frequency network activity has been produced in vitro by changing extracellular medium composition, by using pro-epileptic substances, or by electrical stimulation. Here we study the propagation of these events between different subregions of the male rat hippocampus in a recently introduced experimental model of FRs in entorhinal cortex–hippocampal slices in vitro. By using a matrix of 4096 microelectrodes, the sites of initiation, propagation pathways, and spatiotemporal characteristics of activity patterns could be studied with unprecedented high resolution. To this end, we developed an analytic tool based on bidimensional current source density estimation, which delimits sinks and sources with a high precision and evaluates their trajectories using the concept of center of mass. With this methodology, we found that FRs can arise almost simultaneously at noncontiguous sites in the CA3-to-CA1 direction, underlying the spatial heterogeneity of epileptogenic foci, while continuous somatodendritic waves of activity develop. An unexpected, yet important propagation route is the propagation of activity from CA3 into the hilus and dentate gyrus. This pathway may cause reverberating activation of both regions, supporting sustained pathological network events and altered information processing in hippocampal networks.
Entorhinal cortex (EC) projections to the hippocampus run along the perforant path and activate the hippocampal area CA3 and the dentate gyrus (DG), which, in turn, drives CA3. Because cortical trauma damages the source of inputs to the hippocampus, we hypothesize that such an event can be reflected in immediate alterations of the hippocampal oscillatory activity. We here explore whether acute, localized disruption of EC-EC connectivity is involved in the generation or modulation of high frequency oscillations (HFO) in the hippocampus. We conducted in vitro electrophysiological recordings in CA3 and DG of combined EC-hippocampal transversal slices prepared from intact brains and from brains with a spatially defined, transversal cut of the EC made in situ, 2hours before in vitro recordings commenced. We also determined if pharmacological manipulations of the adenosine system modulated the fast oscillatory activity. EC-hippocampal slices prepared from brains, in which a transversal lesion of the EC was uni- or bilaterally conducted in situ, displayed spontaneous epileptiform events with superimposed ripples (150-250Hz) and fast ripples (>250Hz), whereas those obtained from non-lesioned brains did not have spontaneous HFO. However, in the latter, high frequency stimulation applied to the perforant path produced ripple activity in area CA3. Spontaneous fast ripples were prevented by conducting the slicing procedure and incubating the slices both in a Na(+)-free medium and in a low Ca(++)-high Mg(++) medium for an hour before recording commenced, under normal Na(+) concentration. Activation of A1, but not A2, receptors produced a strong inhibition of the incidence and spectral power of fast ripples but did not change their intrinsic frequency. Our data show that the disruption of EC-to-EC connections can immediately disinhibit hippocampal CA3 area to generate HFO on top of epileptiform events, probably constituting an irritating focus long before overt epileptic activity can be detected behaviorally. Therefore, the activation of the adenosinergic system can possibly be regarded as an immediate intervention strategy to avoid epileptogenesis.
Copyright © 2015. Published by Elsevier Inc.
