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== Sektion für Experimentelle Anaesthesiologie - Kortikale Informationsverarbeitung ==
== Sektion für Experimentelle Anaesthesiologie - Kortikale Informationsverarbeitung ==
=== Project 1 ===
'''Cholinergic modulation of GABAergic inhibition in neocortex'''
Acetylcholine (ACh), a neuromodulator vital to vigilance and cognition, is classically associated with an 'activating' or excitatory function in neocortex. However, ACh excites not only glutamatergic neurons, but also certain classes of inhibitory interneurons. The project is aimed at elucidating in which manner the cholinergic status of cortical networks alters GABAergic inhibition.
We start from the working hypothesis that interneurons sensitive to ACh activate GABA(A) receptors with a subunit composition and pharmacological profile different from that of receptors postsynaptic to ACh-insensitive interneurons. Furthermore, presynaptic modulation of GABA release by ACh may depend on interneuron type. Therefore, the degree of cholinergic activation should govern the contribution of different interneuron types and GABA(A) receptor subtypes to inhibition in cortical networks in multiple ways. We pursue this idea by comparing population activity patterns, inhibitory currents and activity profiles of interneurons in cortical networks in vitro subjected to different conditions of cholinergic stimulation and blockade.
Funded by DFG (HE 6210/1-1)
=== Project 2 ===
'''Enhancing spillover of GABA to peri- und extrasynaptic GABA(A) receptors – a possible route to anesthesia?'''
GABA is the major inhibitory transmitter in the mammalian central nervous system. At synaptic terminals of GABAergic neurons it reaches peak concentrations in the millimolar range, activating synaptic GABA(A) receptors. After release, GABA is very efficiently taken up by GABA transporters (GAT). These membrane-bound transporters, particularly GAT-1, are localized close to the synaptic release sites of GABA. The transporters' activity both curtails the duration of the GABA pulses in the synaptic cleft and restrains spillover of GABA out of the synaptic cleft.


'''Die β3-Untereinheit des GABAA-Rezeptors als Determinante hippokampaler Rhythmen'''
In the light of this pivotal function of GAT we hypothesize that impeding their uptake capacity should have strong inhibitory effects on cortical networks. Specifically, inhibition of GAT-1 very likely enhances the concentration and the dwell time of GABA molecules in and around the synaptic cleft. This enhanced prevalence of GABA should activate (or enhance activation of) GABA(A) receptors which experience subsaturating concentrations of GABA. Most likely, these are peri- and extrasynaptic receptors, which are far away from the sites of GABA release. Depending on the degree of saturation of the synaptic receptors under normal conditions, these may also benefit from a more sluggish removal of GABA.


θ-(4-12 Hz) und γ-(30-80) Oszillationen gehören zu den prominentesten Rhythmen im Hippokampus von Nagern. Sie interagieren: γ-'Bursts' erscheinen vorzugsweise in fixen Phasen von θ. Es wird vermutet, dass diese spezielle Art der Phasenkoppelung für die Verarbeitung von Sinnesreizen und die Bildung von Gedächtnisinhalten wichtig ist.
We probe these hypotheses by exposing spontaneously active cortical networks in vitro to inhibitors of GAT, and by assessing the changes in GABA(A) receptor-mediated currents and activity patterns.
θ- und γ-Oszillationen werden von einer Vielzahl spannungs- und transmittergesteuerter Leitfähigkeiten erzeugt; unter letzteren spielen GABAA Rezeptor-vermittelte Ströme eine wichtige Rolle. In Neuronen der Area CA1 des Hippokampus gibt es zwei verschiedene Arten von GABAA Rezeptor-vermittelten Strömen, die sich in Kinetik, pharmakologischem Profil und räumlicher Verteilung unterscheiden: GABAA, fast, hervorgerufen durch somanahe Synapsen, und GABAA,slow, welches in den distalen Dendriten von Pyramidenzellen generiert wird und eine weitaus längere Abklingzeit aufweist (~80 ms). Es wird vermutet, dass GABAA,slow θ-Oszillationen nicht nur generiert, sondern auch mit γ-Oszillationen koordiniert. Da GABAA,slow vom Vorhandensein von GABAA-Rezeptoren mit β3-Untereinheiten abhängt, verwenden wir Mutanten dieser Untereinheit, um ihre Rolle bei der Erzeugung hippokampaler Rhythmen zu ermittlen. Es handelt sich um 'Knockout'-Mäuse, denen die β3-Untereinheit fehlt, und um 'Knockin'-Mäuse, die eine Punktmutation in der β3-Untereinheit vorweisen, die sie gegenüber dem Anästhetikum Etomidat insensitiv macht. Multielektrodenableitungen im Hippokampus von Knockout-Mäusen lassen vermuten, dass die β3-Untereinheit in der Tat nicht nur für die Ausprägung von θ- und γ-Oszillationen wichtig ist, sondern auch für deren Koordination. Im weiteren Verlauf des Projekts sollen die Effekte von Etomidat auf die Rhythmen in Knockin-Mäusen untersucht werden. Die Resultate sollten Rückschlüsse auf die Modulation von θ- und γ-Oszillationen durch Anästhetika zulassen, die über GABAA-Rezeptoren wirken.


== Weitere Schwerpunkte ==
== Weitere Schwerpunkte ==
   
   
*[[Experimental_Anaesthesiology_Antkowiak_Lab:Subtypes | GABAA-Rezeptor-Subtypen und Anästhesie]]
*[[Experimental_Anaesthesiology_Antkowiak_Lab:Subtypes | GABA(A)-Rezeptor-Subtypen und Anästhesie]]
*[[Experimental_Anaesthesiology_Antkowiak_Lab:SpinalCord |Spinale Mechanismen der Anästhesie]]
*[[Experimental_Anaesthesiology_Antkowiak_Lab:SpinalCord |Spinale Mechanismen der Anästhesie]]

Latest revision as of 02:32, 4 June 2014

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Sektion für Experimentelle Anaesthesiologie - Kortikale Informationsverarbeitung

Project 1

Cholinergic modulation of GABAergic inhibition in neocortex

Acetylcholine (ACh), a neuromodulator vital to vigilance and cognition, is classically associated with an 'activating' or excitatory function in neocortex. However, ACh excites not only glutamatergic neurons, but also certain classes of inhibitory interneurons. The project is aimed at elucidating in which manner the cholinergic status of cortical networks alters GABAergic inhibition.

We start from the working hypothesis that interneurons sensitive to ACh activate GABA(A) receptors with a subunit composition and pharmacological profile different from that of receptors postsynaptic to ACh-insensitive interneurons. Furthermore, presynaptic modulation of GABA release by ACh may depend on interneuron type. Therefore, the degree of cholinergic activation should govern the contribution of different interneuron types and GABA(A) receptor subtypes to inhibition in cortical networks in multiple ways. We pursue this idea by comparing population activity patterns, inhibitory currents and activity profiles of interneurons in cortical networks in vitro subjected to different conditions of cholinergic stimulation and blockade.

Funded by DFG (HE 6210/1-1)

Project 2

Enhancing spillover of GABA to peri- und extrasynaptic GABA(A) receptors – a possible route to anesthesia?

GABA is the major inhibitory transmitter in the mammalian central nervous system. At synaptic terminals of GABAergic neurons it reaches peak concentrations in the millimolar range, activating synaptic GABA(A) receptors. After release, GABA is very efficiently taken up by GABA transporters (GAT). These membrane-bound transporters, particularly GAT-1, are localized close to the synaptic release sites of GABA. The transporters' activity both curtails the duration of the GABA pulses in the synaptic cleft and restrains spillover of GABA out of the synaptic cleft.

In the light of this pivotal function of GAT we hypothesize that impeding their uptake capacity should have strong inhibitory effects on cortical networks. Specifically, inhibition of GAT-1 very likely enhances the concentration and the dwell time of GABA molecules in and around the synaptic cleft. This enhanced prevalence of GABA should activate (or enhance activation of) GABA(A) receptors which experience subsaturating concentrations of GABA. Most likely, these are peri- and extrasynaptic receptors, which are far away from the sites of GABA release. Depending on the degree of saturation of the synaptic receptors under normal conditions, these may also benefit from a more sluggish removal of GABA.

We probe these hypotheses by exposing spontaneously active cortical networks in vitro to inhibitors of GAT, and by assessing the changes in GABA(A) receptor-mediated currents and activity patterns.

Weitere Schwerpunkte

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