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Synaptic transmission of hippocampal mossy fibres in health and diseaseLalic, Tatjana January 2009 (has links)
Dentate microcircuitry is thought to be involved in filtering, integrating, and relaying extrinsic hippocampal inputs to the hippocampus proper, which contributes to memory formation and retrieval. The axons of granule cells are called mossy fibres (MFs), and contain multiple terminal types that form characteristic synaptic connections with their postsynaptic targets. This diversity of presynaptic release sites that exists on the same MF provides an extremely interesting axonal type to study the organizing principles of presynaptic release regulation. A remarkable set of neurotransmitters and receptors present at the MF synaptic complex allow diverse computational modification of information from the dentate gyrus to the hippocampus. There are several types of glutamate receptors expressed at MF, such as group II/III mGluRs and kainate receptors (KARs). Presynaptic KARs modulate transmission at MF-CA3 pyramidal cell synapses; however, it is not known whether presynaptic KARs affect other synapses made by MFs. The aim of the first part of this thesis was to establish the principles of synapse-specific actions of presynaptic KARs in MFs. Combining electrophysiology and calcium imaging, this study provides compelling evidence that presynaptic KARs and Ca<sup>2+</sup> stores can be activated by glutamate release from a single action potential in a single MF axon. This contributes to short-term, use-dependent facilitation of presynaptic Ca<sup>2+</sup> entry and glutamate release exclusively at MF-CA3 pyramidal cell synaps, but not at other MF synapses, on hilar mossy cells or interneurons. Thus, our findings indicate that the presynaptic KARs, coupled with intracellular stores, exist in a synapse-specific autoreceptor mechanism. Activation of KARs strengthened MF-CA3 pyramidal cell synapses by increasing the Ca<sup>2+</sup> influx at giant boutons, which might also contribute to the KAR-dependent hyper-excitability of the MF circuitry related to the mechanisms of temporal lobe epilepsy (TLE). This makes KARs good potential targets for therapies in CNS disorders such as epilepsy and other neurological and psychiatric disorders. The second part of this thesis was to explore the actions on the hippocampus of purified antibodies from a limbic encephalitis (LE) patient. LE is a CNS disease characterized by subacute onset of memory loss and temporal lobe seizures. The serum of these patients strongly labels MFs apparently co-localizing with the VGKC. The patients improve with immunotherapies that reduce the VGKC antibody levels in the serum, thus, strongly suggesting that these antibodies cause the condition. We found that LE serum IgGs enhance CA3 pyramidal cell excitability by blocking α-DTX sensitive VGKCs, which results in the increased release of glutamate. This, in turn, strengthens and desynchronizes MF and CA3 pyramidal cells synaptic transmission. However, these effects were occluded by α-DTX, a Kv1.1, Kv1.2 and Kv1.6 antagonist which, when applied alone, mimicked the action of the LE IgG, suggesting that they may share similar mechanisms of action. In contrast serum taken from healthy control patients had no significant effect under same recording conditions. Thus, this study provides the first evidence that the LE IgG functionally affects VGKC containing Kv1.1, Kv1.2 and/or Kv1.6 at both presynaptic MF axon terminals as well as the postsynaptic somatodendritic domain of CA3 pyramidal cells. Whatever defines the exact nature of LE IgG action, our results suggest that drugs acting specifically as openers of VGKC might help to protect the hippocampus from immune-mediated damage. In conclusion my data is consistent with the increasingly documented idea that MFs play a critical role in regulating the excitability of the hippocampal circuits and the dysfunction of MF transmission profoundly impairs hippocampal function.
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Modulation of cerebellar Purkinje cell discharge by subthreshold granule cell inputs / Modulation de la décharge des cellules de Purkinje du cervelet par des entrées sous-seuils des cellules des grainsGrangeray-Vilmint, Anais 02 June 2016 (has links)
La décharge des cellules de Purkinje (CP), neurone de sortie du cortex cérébelleux, joue un rôle majeur dans le contrôle moteur. Les CP reçoivent des entrées excitatrices provenant des cellules des grains (CG), lesquelles génèrent également une inhibition antérograde sur les CP via l’activation d’interneurones de la couche moléculaire (IN). Lors de ma thèse, j’ai étudié l’influence simultanée de la balance excitation-inhibition (E/I) et des plasticités à court terme aux synapses CG-IN-CP sur la décharge des CP, par des techniques d’électrophysiologie, d’optogénétique et de simulation. Ces travaux démontrent l’existence d’une hétérogénéité d’E/I dans le cortex cérébelleux ainsi qu’une grande diversité de modulation des CP en réponse à la stimulation de CG. Le nombre de stimulation des CG influence fortement la direction et l’intensité de la modulation observée. Enfin, la combinaison de plasticités à court terme et d’E/I génère dans la décharge des CP des motifs de réponses complexes mais reproductibles, ayant sans doute un rôle essentiel dans l’encodage sensoriel. / Rate and temporal coding in Purkinje cells (PC), the sole output of the cerebellar cortex, play a major role in motor control. PC receives excitatory inputs from granule cells (GC) which also provide feedforward inhibition on PC through the activation of molecular layer interneurons (MLI). In this thesis, I studied the influence of the combined action of excitation/inhibition (E/I) balance and short-term plasticity of GC-MLI-PC synapses on PC discharge, by using electrophysiological recordings, optogenetic stimulation and modelling. This work demonstrates that E/I balances are not equalized in the cerebellar cortex and showed a wide distribution of PC discharge modulation in response to GC inputs, from an increase to a shut down of the discharge. The number of stims in GC bursts strongly controls the strength and sign of PC modulation. Lastly, the interplay between short-term plasticity and E/I balance implements complex but reproducible output patterns of PC responses to GC inputs that should play a key role in stimulus encoding by the cerebellar cortex.
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