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. Jörg Geiger
MPI für Hirnforschung
Deutschordenstr. 46
60528 Frankfurt
geiger@mpih-frankfurt.mpg.de

Title

Synaptic plasticity in hippocampal interneuron networks

Question of the project

We are particularly interested in short- and long-term synaptic plasticity mechanisms within inhibitory microcircuits in the hippocampus. We aim to identify the requirements to induce interneuron plasticity under various conditions. The identification of molecular mechanisms underlying interneuron plasticity may enable the specific control of inhibitory microcircuits in the future.

Current State of Research

A central element of neuronal signal processing and plasticity is the regulation of transmission strength at chemical synapses. Fast-spiking inhibitory interneurons contribute essentially to rapid synchronization and the generation of oscillations in hippocampal networks (Bartos et al., 2002; Fuchs et al., 2001, 2007). A selective reduction of the excitatory drive to fast-spiking inhibitory interneurons leads to an impairment of gamma-frequency oscillations and working memory (Fuchs et al., 2007). Recently, long-term synaptic plasticity mechanisms have been discovered in inhibitory microcircuits in the hippocampus and neocortex (Alle et al., 2001, Holmgren and Zilberter, 2001, Lamsa and Kullmann, 2007). Particularly excitatory synaptic transmission onto inhibitory interneurons can undergo long-lasting bi-directional alterations depending on induction mechanisms (Alle et al., 2001). However, the present literature suggests that the properties of interneuron plasticity depend on interneuron subtype, induction protocol and hippocampal sub-region (Lamsa and Kullmann, 2007). The molecular mechanisms underlying the different types of interneuron plasticity are still largely unknown.

Alle, H., Jonas, P. and Geiger, J.R.P. (2001). PTP and LTP at a hippocampal mossy fiber - interneuron synapse. Proc. Natl. Acad. Sci. USA, 98, 14708-14713.
Bartos, M., Vida, I., Frotscher, M., Meyer, A., Monyer, H., Geiger, J.R.P. and Jonas, P. (2002). Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks. Proc. Natl. Acad. Sci. USA, 99, 13222-13227.
Fuchs, EC, Doheny, H, Faulkner, H, Caputi, A, Traub RD, Bibbig, A, Kopell, N, Whittington, MA, Monyer, H (2001). Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation. Proc Natl Acad Sci USA. 98:3571-6.
Fuchs, EC, Zivkovic, AR, Cunningham, MO, Middleton, S, Lebeau, FE, Bannerman, DM, Rozov, A, Whittington, MA, Traub RD, Rawlins, JN, Monyer, H. (2007). Recruitment of parvalbumin-positive interneurons pyramidical cells. Neuron. 53: 591-604.
Holmgren CD, Zilberter Y. Coincident spiking activity induces longterm changes in inhibition of neocortical pyramidical cells. J Neuroscience 2001, 21: 8270-7.
Kullmann DM, Lamsa KP. (2007) Long-term synaptic plasticity in hippocampal interneuons. Nat Rev Neurosci. 8, 687-99.

3.3.4 Eigene Vorarbeiten/ Previous work of the group in the field

We study the cellular physiology of fast-spiking interneurons in the dentate gyrus of rodent hippocampal formation using acute brain slices (Koh et al., 1995). In a combined electrophysiological and single cell RT-PCR study we found that fast-spiking interneurons largely lack the expression of the GluR-2 AMPA-receptor subunit causing fast kinetics and high Ca 2+ -permeability of AMPA receptors (Geiger et al. 1995; Koh et al. 1995) . Paired recordings with the high resolution patch-clamp technique of synaptically coupled principal neurons and fast-spiking interneurons showed that glutamatergic synaptic excitation of fast-spiking interneurons is characterized by a submillisecond AMPA receptor-mediated signalling which enables these interneurons to act as coincidence detectors of principal cell activity (Geiger et al. 1997) and to provide a timely precise inhibitory output signal to principal cells (Hefft et al., 2002) to synchronize principal cell ensembles. In addition, fast-spiking interneurons form highly interconnected networks. They excite each other by gap junctions and inhibit each other by fast GABAergic inhibition (Bartos et al. 2001; Bartos et al. 2002) . These specific properties of synaptic input and the strategic positioning of fast-spiking inteneurons in local networks controlling the activity of principal cells enables these interneuron networks to synchronize the activity of principal cell ensembles in the beta- and gamma-frequency range (Bartos et al. 2002) . At glutamatergic n synapses onto fast-spiking interneurons in the dentate gyrus, we discovered bidirectional long-term plasticity (Alle et al. 2001) . Long-term potentiation (LTP) was elicited by an associative gamma-frequency induction protocol (30 Hz). Long-term depression (LTD) was elicited by a non-associative gamma-frequency induction protocol (30 Hz). We could further show that induction of long-lasting plasticity was in the postsynaptic interneuron but the expression of long-lasting plasticity presynaptic mechanisms indicating the involvement of retrograde messengers which still need to be identified. The next steps analysing synaptic plasticity in fast-spiking interneuron networks are the identification of the underlying molecular mechanisms, the role of naturally occurring activity patterns for induction of synaptic plasticity, the analysis of long-term synaptic plasticity at inhibitory synapses and of gap junction couplings and, finally, the computational analysis of plasticity in fast-spiking interneuron networks for hippocampal information processing.

Alle, H., Jonas, P. and Geiger, J.R.P. (2001). PTP and LTP at a hippocampal mossy fiber - interneuron synapse. Proc. Natl. Acad. Sci. USA, 98, 14708-14713.
Bartos, M., Vida, I., Frotscher, M., Meyer, A., Monyer, H., Geiger, J.R.P. and Jonas, P. (2002). Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks. Proc. Natl. Acad. Sci. USA, 99, 13222-13227.
Bartos, M., Vida, I., Frotscher, M., Geiger, J.R.P. and Jonas, P. (2001). Rapid signaling at inhibitory synapses in a dentate gyrus network. J. Neurosci., 21, 2687-2698.
Geiger, J.R.P., Lübke, J., Roth, A., Frotscher, M. and Jonas, P. (1997). Submillisecond AMPA-receptor-mediated signaling at a principal neuron-interneuron synapse. Neuron, 18, 1009-1023.
Geiger, J.R.P., Melcher, T., Koh, D.-S., Sakmann, B., Seeburg, P.H., Jonas, P. and Monyer, H. (1995). Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 15, 193-204.
Hefft, S., Kraushaar, U., Geiger, J.R.P. and Jonas, P. (2002). Presynaptic short-term depression is maintained during regulation of transmitter release at a GABAergic synapse in rat hippocampus. J. Physiol. , 539, 201-208.
Koh, D.-S., Geiger, J.R.P., Jonas, P. and Sakmann, B. (1995). Ca2+ permeable AMPA and NMDA receptor channels in dentate gyrus basket cells of rat hippocampus. J. Physiol. 485, 383-402.

Methods

Patch-clamp technique in acute brain slices of rodents including multiple recordings of synaptically connected neurons; single cell RT-PCR, computer simulations using NEURON, ion channel analysis in brain slices and in expression systems, Ca2+-imaging, immunocytochemistry and morphological reconstructions.

Dissertation topics

Dissecting pre- and postsynaptic correlates underlying synaptic long-term plasticity in fast-spiking interneurons
Role of NMDA receptors in interneuron plasticity
Synaptic plasticity of mutual interactions between fast-spiking interneurons
Synaptic plasticity in interneuron networks induced by naturally occurring activity patterns
Contribution of synaptic plasticity in interneurons to the generation of coherent network activity

Cooperation with other Members

AG Heinemann/Kempter: Interneuron plasticity in interneuron network models of gamma-frequency oscillations.
AG Schmitz/Brecht: Quantitative comparison of synaptic plasticity at mossy fiber- pyramidal cell synapses and mossy fiber- interneuron synapses; in vivo recordings of fast-spiking interneuron activity in behaving animals.
AG Sigrist: Presynaptic structural elements contributing to mossy fiber-interneuron plasticity

Scholarship Holder:

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