Freie Universität Berlin
Charité University Medicine Berlin
Humboldt University Berlin
Max-Delbrück-Center for Molecular Medicine, Berlin-Buch
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GRK 1123:

Cellular Mechanisms of Learning and Memory Consolidation
in the Hippocampal Formation

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This Research Training Group is funded by the German Research Council DFG

©2006, FU Berlin
GRK 1123

Imprint & Disclaimer
AG Ahnert-Hilger AG Behr AG Braunewell AG Haucke AG Heinemann
AG Kempermann AG Kempter/Schmitz AG Kuhl AG Multhaup AG Nitsch

PD Dr. rer. nat. Richard Kempter
ITB, Theoretical Neuroscience
Humboldt Universität zu Berlin
Invalidenstr. 43
10115 Berlin
r.kempter@biologie.hu-berlin.de


Prof. Dr. med. Dietmar Schmitz
Neurowissenschaftliches Forschungszentrum
Charité Universitätsmedizin Berlin
Schumannstr. 20/21
10117 Berlin
dietmar.schmitz@charite.de


Title

Quantitative description of synaptic plasticity at the hippocampal mossy fiber synapse

Question of the project

Synapses exhibit strikingly different forms of plasticity over a wide range of time scales, from milliseconds to hours. We are particularly interested in the functional roles of both short-term and long-term activity-dependent changes in synaptic parameters such as strength, release probability, and time constants of depression and facilitation. Our project is focusing on the hippocampal mossy fiber synapse.

Scientific background

A common feature of excitatory synapses is that brief repetitive activity initiates long-lasting changes in synaptic strength. The most common and well-studied form of long-lasting synaptic plasticity is NMDAR-dependent LTP, which requires the activation of postsynaptic NMDARs and a rise in postsynaptic calcium (Malenka & Nicoll, 1999). The voltage-dependence of the NMDAR imparts an associativity to this form of plasticity, such that a weak tetanus that fails to elicit LTP alone can do so when it is combined with a strong tetanus to neighboring synapses. Hippocampal mossy fiber synapses also show LTP, but this form of LTP is entirely independent of NMDAR activation (Harris & Cotman, 1986; Zalutsky & Nicoll, 1990). Although there is not unanimous agreement, considerable evidence suggests that mossy fiber LTP is both induced and expressed presynaptically. More specifically, mossy fiber LTP can be induced in the presence of the ionotropic glutamate receptor antagonists CNQX or kynurenate, which block AMPARs and KARs. It can also be induced in the combined presence of kynurenate and metabotropic glutamate receptor (mGluR) antagonists. This has led to a model in which the induction of mossy fiber LTP depends on a tetanus-induced rise in presynaptic calcium (Castillo et al., 1994; Nicoll & Malenka, 1995). In addition to LTP, mossy fiber synapses show an unusual form of short-term synaptic plasticity (STP), in which low frequency activation causes a several fold increase in synaptic transmission (Salin et al., 1996).


Previous work of the group in the field

Hippocampal mossy fibers, which are the axons of dentate granule cells, form powerful excitatory synapses onto the proximal dendrites of CA3 pyramidal cells. We and others found that the synaptic release of glutamate from mossy fibers activates presynaptic KARs, causing an enhancement of the fiber volley and a facilitation of release (Contractor et al, 2001, Lauri et al, 2001; Schmitz et al, 2000; Schmitz et al, 2001a, b). This positive feedback contributes to the dramatic frequency facilitation that is characteristic of mossy fiber synapses (Schmitz et al, 2001b). Moreover, we recently provided evidence that these presynaptic KARs impart an associative property to hippocampal mossy fiber LTP by setting the induction-threshold (Schmitz et al, 2003).

Hippocampal mossy fiber long-term potentiation (LTP) is expressed presynaptically, but the exact mechanisms remained unknown. We recently demonstrated the involvement of the hyperpolarization-activated cation channel (Ih) in the expression of mossy fiber LTP (Mellor et al, 2002). Established LTP was blocked and reversed by Ih channel antagonists (Mellor et al, 2002; see also Huang & Hsu, 2003). Most important, whole-cell recording from granule cells revealed that repetitive stimulation causes a calcium- and Ih-dependent long-lasting depolarization mediated by protein kinase A. Depolarization at the terminals would be expected to enhance transmitter release, whereas somatic depolarization would enhance the responsiveness of granule cells to afferent input. Thus, Ih channels play an important role in the long-lasting control of transmitter release and neuronal excitability.

The release properties of synapses in the central nervous system vary greatly, not only across anatomically distinct types of synapses but also among the same class of synapse. This variation manifests itself in large part by differences in the probability of transmitter release, which affects activity-dependent presynaptic forms of plasticity such as paired-pulse facilitation and frequency facilitation. We showed that the unique presynaptic properties of the hippocampal mossy fiber synapse are largely imparted onto the synapse by the continuous local action of extracellular adenosine at presynaptic A1 adenosine receptors, which maintains a low basal probability of transmitter release (Moore et al, 2003).

Presynaptic forms of LTP require a rise in the intraterminal calcium concentration, but the channel through which calcium passes has not been identified. By using pharmacological tools as well as genetic deletion, we recently demonstrated that alpha1E-containing voltage-dependent calcium channels (VDCCs) shift the threshold for mossy fiber LTP (Breustedt et al, 2003). The channel is not involved in the expression mechanism, but it contributes to the calcium influx during the induction phase. Indeed, optical recordings directly show the presence and the function of alpha1E-containing VDCCs at mossy fiber terminals. Hence, a previously undescribed role for alpha1E-containing VDCCs is suggested by these results.

Goals

Focusing on the highly plastic mossy-fiber synapse, which provides the main feed-forward input to the hippocampal CA3 region, we will use in vivo activity patterns and specifically tailored irregular spike trains to study how plasticity depends on the precise time structure of presynaptic inputs. We will then develop a biophysically motivated model of the synapse. Principal and Independent Component Analysis of the highly variable excitatory postsynaptic potentials will improve the quantitative description of the synapse, and thus us help to evaluate its role for information processing in the hippocampus.

Methods

Dissertation topics


Cooperation with other Members  


Scholarship Holder:

 

AG Ahnert-Hilger AG Behr AG Braunewell AG Haucke AG Heinemann
AG Kempermann AG Kempter/Schmitz AG Kuhl AG Multhaup AG Nitsch