GRK 1123 - Learning and Memory

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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

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AG Ahnert-Hilger	AG Behr	AG Geiger	AG Haucke	AG Heinemann/ Kempter
AG Multhaup	AG Wulczyn	AG Rosenmund	AG Schmitz/ Brecht	AG Sigrist

Prof. Dr. Dietmar Schmitz
Neurowissenschaftliches Forschungszentrum
Charité Universitätsmedizin Berlin
Charitéplatz 1
10117 Berlin
dietmar.schmitz@charite.de

Prof. Dr. Michael Brecht
Bernstein Center for Computational Neuroscience
Humboldt Universität zu Berlin
Philippstr. 13, House 6
10115 Berlin
michale.brecht@bccn-berlin.de

Topic

Natural spike trains and plasticity

Title

Induction of synaptic plasticity by natural spike trains within the hippocampal formation

Issues of the project

A common feature of most glutamatergic synapses is their ability to undergo activitydependent long-lasting changes in synaptic strength. Studies on synaptic plasticity typically use constant-frequency stimulation to activate synapses, whereas in vivo activity of neurons is irregular. In our project we will investigate the effect of natural spike trains on synaptic plasticity at two different glutamatergic synapses within the hippocampal formation.

Current State of Research

Long-lasting changes in the strength of connections between neurons are assumed to underlie the encoding and storage of memory traces in the central nervous system (Bliss and Collingridge, 1993; Malenka and Nicoll, 1999; Martin et al., 2000). This ‘synaptic plasticity-memory’-hypothesis (Martin et al., 2000; Martin and Morris, 2002) is mainly based on two lines of arguments. First, interventions that prevent the induction (Nakazawa et al., 2003; Nakazawa et al., 2004) or expression (Rumpel et al., 2005) of changes in synaptic weight impair memory in animals (Nakazawa et al., 2004; Rumpel et al., 2005) as well as in humans (Grunwald et al., 1998). Second, physiological properties of synaptic plasticity like input-specificity, persistency and associativity are often linked to information storage mechanisms (Martin et al., 2000; Martin and Morris, 2002). At most synapses throughout the central nervous system synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) relies on the activation of postsynaptic NMDA receptors (Bear, 1996; Bliss and Collingridge, 1993; Malenka and Bear, 2004; Nicoll and Malenka, 1995), which endows these forms of plasticity with an associative component (Bliss and Collingridge, 1993; Malenka and Nicoll, 1999). Importantly though, also NMDAR-independent LTP has been found at various types of glutamatergic synapses (Castro-Alamancos and Calcagnotto, 1999; Harris and Cotman, 1986; Nicoll and Schmitz, 2005; Salin et al., 1996a; Zalutsky and Nicoll, 1990), but the functional role of this form of synaptic plasticity is not known (Henze et al., 2000).

Bear MF (1996) NMDA-receptor-dependent synaptic plasticity in the visual cortex. Prog Brain Res 108: 205-218.
Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361: 31-39.
Castro-Alamancos MA, Calcagnotto ME (1999) Presynaptic long-term potentiation in corticothalamic synapses. J Neurosci 19: 9090-9097.
Grunwald T, Lehnertz K, Heinze HJ, Helmstaedter C, Elger CE (1998) Verbal novelty detection within the human hippocampus proper. Proc Natl Acad Sci USA 95: 3193-3197.
Harris EW, Cotman CW (1986) Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl D-aspartate antagonists. Neurosci Lett 70: 132-137.
Henze DA, Urban NN, Barrionuevo G (2000) The multifarious hippocampal mossy fiber pathway: a review. Neuroscience 98: 407-427.
Malenka RC, Nicoll RA (1999) Long-term potentiation--a decade of progress? Science 285: 1870-1874.
Martin SJ, Grimwood PD, Morris RG (2000) Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23: 649-711.
Martin SJ, Morris RG (2002) New life in an old idea: the synaptic plasticity and memory hypothesis revisited. Hippocampus 12: 609-636.
Nakazawa K, McHugh TJ, Wilson MA, Tonegawa S (2004) NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci 5: 361-372.
Nakazawa K, Sun LD, Quirk MC, Rondi-Reig L, Wilson MA, Tonegawa S (2003) Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38: 305-315.
Nicoll RA, Schmitz D (2005) Plasticity at the hippocampal mossy fibre synapse. Nature Rev Neurosciences.
Rumpel S, LeDoux J, Zador A, Malinow R (2005) Postsynaptic receptor trafficking underlying a form of associative learning. Science 308: 83-88.
Salin PA, Malenka RC, Nicoll RA (1996a) Cyclic AMP mediates a presynaptic form of LTP at cerebellar parallel fiber synapses. Neuron 16: 797-803.
Salin PA, Scanziani M, Malenka RC, Nicoll RA (1996b) Distinct short-term plasticity at two excitatory synapses in the hippocampus. Proc Natl Acad Sci USA 93: 13304-13309.
Zalutsky RA, Nicoll RA (1990) Comparison of two forms of long-term potentiation in single hippocampal neurons. Science 248: 1619-1624.

Previous work of the group

The modulation of synaptic transmission by presynaptic ionotropic and metabotropic receptors is an important means to control and dynamically adjust synaptic strength. Even though synaptic transmission and plasticity at the hippocampal mossy fibre synapse are tightly controlled by presynaptic receptors, little is known about the downstream signalling mechanisms and targets of the different receptor systems. In the present study, we identified the cellular signalling cascade by which adenosine modulates mossy fibre synaptic transmission. By means of electrophysiological and optical recording techniques, we found that adenosine activates presynaptic A1 receptors and reduces Ca2+ influx into mossy fibre terminals. Ca2+ currents are directly modulated via a membrane-delimited pathway and the reduction of presynaptic Ca2+ influx can explain the inhibition of synaptic transmission. Specifically, we found that adenosine modulates both P/Q- and N-type presynaptic voltage-dependent Ca2+ channels and thereby controls transmitter release at the mossy fibre synapse.

Synapses continuously experience short- and long-lasting activity-dependent changes in synaptic strength. Long-term plasticity refers to persistent alterations in synaptic efficacy, whereas short-term plasticity (STP) reflects the instantaneous and reversible modulation of synaptic strength in response to varying presynaptic stimuli. The hippocampal mossy fibre synapse onto CA3 pyramidal cells is known to exhibit both a presynaptic, NMDA receptor-independent form of long-term potentiation (LTP) and a pronounced form of STP. A detailed description of their exact interdependence is, however, lacking. Here, using electrophysiological and computational techniques, we have developed a descriptive model of transmission dynamics to quantify plasticity at the mossy fibre synapse. STP at this synapse is best described by two facilitatory processes acting on time-scales of a few hundred milliseconds and about 10 s. We find that these distinct types of facilitation are differentially influenced by LTP such that the impact of the fast process is weakened as compared to that of the slow process. This attenuation is reflected by a selective decrease of not only the amplitude but also the time constant of the fast facilitation. We henceforth argue that LTP, involving a modulation of parameters determining both amplitude and time course of STP, serves as a mechanism to adapt the mossy fibre synapse to its temporal input.

Distinct functional roles in learning and memory are attributed to certain areas of the hippocampus and the parahippocampal region. The subiculum as a part of the hippocampal formation is the principal target of CA1 pyramidal cell axons and serves as an interface in the information processing between the hippocampus and the neocortex. Subicular pyramidal cells have been classified as bursting and regular firing cells. Here we report fundamental differences in long-term potentiation (LTP) between both cell types. Prolonged high-frequency stimulation induced NMDA receptor-dependent LTP in both cell types. While LTP relied on postsynaptic calcium in regular firing neurons, no increase in postsynaptic calcium was required in bursting cells. Furthermore, paired-pulse facilitation revealed that the site of LTP expression was postsynaptic in regular firing neurons, while presynaptic in burst firing neurons. Our findings on synaptic plasticity in the subiculum indicate that regular firing and bursting cells represent two functional units with distinct physiological roles in processing hippocampal output.

Wozny C, Maier N, Fidzinski P, Breustedt J, Behr J, Schmitz D. (2008) Differential cyclic AMP signaling at hippocampal output synapses. J Neurosci.. (in press)
Wozny C, Breustedt J, Wolk F, Varoqueaux F, Boretius S, Zivkovic A, Neeb A, Frahm J, Schmitz D, Brose N, Ivanovic A (2008) The function of glutamatergic synapses is not perturbed by severe knock-down of 4.1N and 4.1G expression. J Cell Sci.. (in press)
Wozny C, Maier N, Schmitz D*, Behr J* (2008) Two different forms of long-term potentiation at CA1-subiculum synapses. J Physiol. (in press) *equal contribution
Leibold, C, Gundlfinger, A, Schmidt, R, Thurley, K, Schmitz D*, Kempter, R* (2008) Temporal coding via synaptic facilitation. Proc Natl Acad Sci USA (in press) *equal contribution
Brecht M, Schmitz D (2008) Rules of plasticity. Science 319:39-40
Gundlfinger A, Leibold C, Gebert K, Moisel M, Schmitz D*, Kempter R* (2007) Differential modulation of short-term synaptic dynamics by long-term potentiation at mouse hippocampal mossy fibre synapses. J Physiol. 585:853-65. *equal contribution
Gundlfinger A, Bischofberger J, Johenning FW, Torvinen M, Schmitz D*, Breustedt J* (2007) Adenosine modulates transmission at the hippocampal mossy fibre synapse via direct inhibition of presynaptic calcium channels. J Physiol. 582:263-77. *equal contribution
Lee, A.K., Manns, I.D., Sakmann, B., Brecht, M.: Whole-cell recordings in freely moving rats. Neuron 51, 399-407 (2006).
Plath N, Ohana O, et al. (2006) Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52:437-444.
Gundlfinger A, Schmitz D. (2005) Inactivity sets XL synapses in motion. Neuron 47(5):623-5. (2005)
Nicoll RA, Schmitz D (2005) Synaptic plasticity at hippocampal mossy fibre synapses. Nature Review Neurosciences 6(11):863-76.
Breustedt J, Schmitz D. (2004) Assessing the role of GLUK5 and GLUK6 at hippocampal mossy fiber synapses. J Neurosci. 24(45):10093-8.
Breustedt J, Vogt KE, Miller RJ, Schmitz D (2004) a1E-containing Ca2+-channels are involved in synaptic plasticity. Proc Natl Acad Sci USA 100(21):12450-12455.
Schmitz D et al. (2004) Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation. Nature Neuroscience 6:1058-1066.

Objectives

We will investigate the effect of natural spike trains on synaptic plasticity at the hippocampal mossy fiber synapse and also at the associational/commissural synapse onto bursting neurons within the subiculum. Both synapses express presynaptic forms of plasticity.

Methods

Elektrophysiological techniques in vitro and in vivo
Data Analysis (together with R. Kempter)

Topics for Thesis Projects

Response of hippocampal mossy fiber synapses to natural spike trains
Induction of short- and longterm synaptic plasticity by irregular acitivity within the subiculum

Cooperation with other Members of the Graduate School

AG Ahnert-Hilger and Behr: Using biochemical as well as electrophysiological techniques, we are currently studying presynaptic mechanisms of LTP and LTD in the hippocampus.
AG Heinemann/Kempter: With the group of Uwe Heinemann we are studying the mechanisms of sharp-wave ripple complexes in the hippocampal formation.
AG Nitsch: The group of Robert Nitsch recently discovered a new plasticity-related gene (PRG-1). The gene is specifically expressed in hippocampal neurons with high expression levels in dentate gyrus granule cells. Since mossy fibers are the axons of these granule cells, it will be of interest to study the physiology and development of mossy fiber synapses in PRG1 knock-out mice.
AG Sigrist: With the research group of S. Sigrist we will study the plasticity at the active zone at the hippocampal mossy fiber synapse.

Scholarship Holders:

Prateep Beed (09/2006 - 08/2009)
Stephanie Wegener (since June 2009)

AG Ahnert-Hilger	AG Behr	AG Geiger	AG Haucke	AG Heinemann/ Kempter
AG Multhaup	AG Nitsch/ Wulczyn	AG Rosenmund	AG Schmitz/ Brecht	AG Sigrist