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Freie
Universität Berlin |
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GRK 1123: |
Cellular Mechanisms of Learning and
Memory Consolidation |
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This Research Training Group is funded by the German Research Council
DFG
Prof. Dr. med. Joachim Behr
Klinik für Psychiatrie und Psychotherapie
CHARITÉ - UNIVERSITÄTSMEDIZIN BERLIN
Campus Charité Mitte
Charitéplatz 1
10117 Berlin
Institut für Neurophysiologie
Oudenarder Str, 16
Haus A, Aufgang 6-11, Etage E3
13347 Berlin
Mobile: 0172 4407431
Fax: +49 (0)30 450-539941
e-mail: joachim.behr@charite.de
http://www.behrlab-charite.de/joachim.behr@charite.de
Topic
Cellular
mechanisms of synaptic plasticity in the hippocampal
formation
Title
Dopaminergic modulation of synaptic plasticity at CA1-subiculum
synapses
Question
of the project
Encoding of novel
information has been proposed to rely on the time-locked release of dopamine in
the hippocampal formation during novelty detection (Lisman and Grace, 2005). The subiculum
is the principal target of CA1 pyramidal cells and functions as an interface
between the hippocampus and the dopaminergic system.
Using electrophysiological and pharmacological approaches, we will investigate
the efficacy of phasic D1/D5-R activation to allow
the induction of LTP at CA1-subiculum synapses.
Current State of Research
Activity-dependent
synaptic plasticity is regarded as one of the cellular mechanisms which
underlie learning and memory. Long-term potentiation
(LTP) is a form of synaptic plasticity that has been differentiated into an
early and late form. Late-LTP is D1/D5-R-dependent (Frey et al., 1990) and
requires activation of the cAMP-PKA cascade (Frey et
al., 1993) and subsequent protein synthesis. Early-LTP is DA-R-independent, but
may be facilitated by activation of D1/D5-R both in vitro (Otmakhova
and Lisman, 1996) and in vivo (Li et al., 2003).
Though the subiculum plays a crucial role in the
encoding of sensory information as well as in the interaction between the
hippocampus and the mesolimbic dopaminergic
system, the cellular mechanisms of dopaminergic
modulation of synaptic transmission (Behr et al., 2000) and plasticity in this
structure are hitherto not understood.
- Behr J, Gloveli T,
Schmitz D, Heinemann U (2000) Dopamine depresses excitatory synaptic
transmission onto rat subicular neurons via presynaptic D1-like dopamine receptors. J Neurophysiol 84: 112-119.
- Frey U, Huang Y-Y, Kandel
ER (1993) Effects of cAMP simulate
a late stage of LTP in hippocampal CA1 neurons. Science 260: 1661-1664.
- Frey U, Schroeder H, Matthies
H (1990) Dopaminergic antagonists prevent
long-term maintenance of posttetanic LTP in the
CA1 region of rat hippocampal slices. Brain Res 522: 69-75.
- Li S, Cullen WK, Anwyl
R, and Rowan MJ. Dopamine-dependent facilitation of LTP induction in the hippocampal CA1 by exposure to spatial novelty. Nat.Neurosci. 6[5], 526-531. 1-5-2003.
- Lisman JE, Grace AA (2005) The hippocampal-VTA loop:
controlling the entry of information into long-term memory. Neuron 46: 703-713.
- Otmakhova NA, Lisman
JE (1996) D1/D5 dopamine receptor activation increases the magnitude of
early long-term potentiation at CA1 hippocampal synapses. J
Neurosci 16: 7478-7486.
Previous Work of the group in the field
• Synaptic plasticity in the subiculum
We showed that subicular pyramidal cells in rodents and in humans can be
differentiated according to their discharge properties into burst-spiking and
regular-spiking cells (Wozny et al., 2003; Wozny et al., 2008). Little is known about the functional
properties of these two cell-types. Our recent work demonstrates that regular
and burst-spiking cells provide two different forms of synaptic plasticity (Fidzinski et al., 2008; Wozny et
al., 2008; Wozny et al., in press; Shor et al., under revision). In regular firing cells,
induction of LTP relies on the activation of postsynaptic NMDA receptors and
subsequent Ca2+-influx. In burst-spiking cells, however, LTP is induced by presynaptic NMDA-R-mediated Ca2+-influx that results in the
activation of the presynaptic cAMP-PKA
cascade. As there is some evidence that regular- and burst-spiking cells
project to different structures in the parahippocampal
region, these cell types represent two functional units with distinct
physiological roles in processing hippocampal output.
• Dopaminergic modulation of
synaptic plasticity in the subiculum
Our work presents
evidence that conditioning activation of D1/D5-R by the specific agonist SKF
39383 facilitates activity-dependent LTP selectively in subicular
burst-spiking neurons but not in CA1 neurons. Our results indicate that the
facilitated LTP is mediated by D1/D5 receptors and requires the activation of NMDA
receptors (s. Description of PhD Project and Research Results - Lisa Roggenhofer). In MK-801 treated rats that show an increased
release of DA in the hippocampus, we also observed a facilitation of LTP in the
subiculum (Buck et al., 2005). Taken together, our
recent work suggests that activation of D1/D5-R causes an increased activation
of presynaptic cAMP that
facilitates the expression of LTP in subicular
burst-spiking cells.
- Buck, N., Cali , S., and
Behr, J. Enhancement of long-term potentiation
at CA1-subiculum synapses in MK-801-treated rats. Neurosci. Lett., 392(1-2):5-9, 2006.
- Fidzinski, P., Shor,
O., and Behr, J. Cell-specific threshold for the induction of
bidirectional synaptic plasticity at hippocampal
output synapses, Eur. J. Neurosci., 27(5):1111-8,
2008.
- Shor O, Fidzinski
P, and Behr J. Muscarinic acetylcholine
receptors and voltage-gated calcium channels contribute to bidirectional
synaptic plasticity at CA1-subiculum synapses. Neurosci.
Lett.,
in press.
- Wozny C, Maier N, Fidzinski P, Breustedt J,
Behr J*, and Schmitz D* (* equal contribution). Differential cyclic AMP
signaling at hippocampal output synapses J. Neurosci., in
press.
- Wozny, C., Maier, N., Schmitz, D*,
and Behr, J* (* equal contribution). Two different forms of long-term potentiation at CA1-subiculum synapses, J. Physiol.,
586 ( 11 ): 2725-34 , 2008.
- Wozny, C., Kivi,
A., Lehmann, T. N., Dehnicke, C., Heinemann, U.,
and Behr, J. Comment on "On the origin of interictal
activity in human temporal lobe epilepsy in vitro". Science, 301(5632): 463, 2003.
Goals
In this grant
proposal we will investigate, whether DA-induced facilitation of LTP in subicular burst-spiking cells relies on the activation of
the presynaptic cAMP-PKA
cascade. As postsynaptic LTP in regular-spiking cells has been shown to be cAMP-PKA-independent, we expect different forms of dopaminergic modulation of synaptic plasticity between
regular- and burst-spiking cells.
We will address
the following issues:
• Effect of DA1/DA5-R-activation on membrane properties
• Ca2+-dependency of D1/D5-R-dependent LTP
• Transduction-mechanisms of D1/D5-R-dependent LTP
• Synaptic site of expression ofD1/D5-R-dependent LTP
Methods
The in-vitro
experiments will be conducted by use of:
• Conventional intracellular single-cell-recordings in
rat hippocampal brain slices
• Whole-cell patch-clamp-recordings with
Infrared-DIC-Video-Microscopy
• Extra- and intracellular application of specific
agonists und antagonists to determine the involved signaling cascades and the
site of LTP expression.
Dissertation topics
- Transduction-mechanisms of D1/D5-R-dependent LTP
at CA1-subiculum synapses
- Expression-mechanisms of D1/D5-R-dependent LTP at
CA1-subiculum synapses
Cooperation with other
Members
·
AG
Heinemann/Kempter: Interaction between entorhinal cortex, hippocampus and subiculum,
role of DA and NE in induction of spharp wave ripple
activity
·
AG
Schmitz/Brecht: Presynaptic forms of synaptic
plasticity in the hippocampal formation
(mossy-fiber-synapse vs. CA1-subiculum synapse)
·
AG Geiger: Changes in synaptic plasticity in
interneuron networks
Scholarship
Holders:
- Nadine Buck (April 2005 - February 2006)
- Oded Shor (January
2006 - December 2008)
- Julia Bartsch (March 2009 -
August 2009)
- Benjamin Wagner (since October 2010)