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

Prof. Dr. phil. Dietmar Kuhl
Institut für molekulare Neurobiologie
Freie Universität Berlin
Takustr. 6
14195 Berlin
kuhl@neuroscience.fu-berlin.de


Title

The role of activity-dependent genes in the consolidation of memories

Question of the project

We are interested in understanding how the transcriptomic and proteomic response of neurons to patterned synaptic activity determines the capability of animals to store memories.

Scientific background

Neurons have the capacity to undergo activity-dependent changes in their molecular composition and structure in order to adjust their synaptic strength (Lamprecht and LeDoux, 2004). Such synaptic plasticity appears to contribute to a variety of physiological and pathological processes in the adult brain including learning and memory, epileptogenesis, responses to ischemia, drug addiction, and neurological diseases (Hyman und Malenka, 2001; Johnston, 2004). Since enduring forms of synaptic plasticity, like long-term potentiation (LTP) and long-term memory require activity-dependent gene induction that is important in defining neuronal connectivity in the brain, it is anticipated that many forms of mental disabilities, including neurodegenerative processes and cognitive disturbances will be understood as cortical or limbic cognates of disturbed activity-dependent gene transcription. Much attention therefore has been focused on the identification and functional characterization of the specific genes that are induced by patterned synaptic activity (Lanahan and Worley, 1998). Some of the recently identified activity-dependent genes appear to play central roles in the molecular reorganization of protein networks at the synaptic membrane specialization, or post-synaptic density (PSD) that occurs as result of plasticity producing stimulation. The membrane-attached PSD concatenates receptors via scaffolding proteins with signaling enzymes as well as the cytoskeleton (Kennedy, 2000). The molecular composition of the PSD is highly dynamic and changes taking place following plasticity-inducing activation include insertion and modification of scaffolding, signaling, and receptor molecules (Grant and O'Dell, 2001; Sheng and Kim, 2002).


Previous work of the group in the field

The main goal of our laboratory is to bring to bear molecular biological approaches for the identification and study of genes contributing to synaptic plasticity in the mammalian brain. In the last several years we have conducted a systematic survey of the alterations in gene expression that occur in hippocampal neurons following synaptic activity (Qian et al., 1993; Konietzko and Kuhl, 1998; Kuhl, 2000). Several of the genes identified in our laboratory play important roles in the activity-dependent changes in synaptic function (Frey et al., 1996; Konietzko et al., 1999; Kauselmann et. al., 1999). A particularly fascinating example can be seen in the expression of Arg3.1 (Link et al., 1995). Arg3.1 is thus far unique among all genes, as its mRNA has the potential to be locally translated at stimulated synapses and consequently might play a key role in synapse-specific modifications (Kuhl and Skehel, 1998) . The induction of Arg3.1 is strictly dependent on the activation of PKA and the MAPK/ERK kinase signaling pathways which have been demonstrated to play specific roles in learning and memory (Waltereit et al., 2001). Moreover, following LTP induction, Arg3.1 protein is selectively localized at stimulated synapses and associates with the NMDA receptor complex at the PSD (Plath et al., 2003). Mice in which we have disrupted the Arg3.1 gene show an enlarged but transient form of LTP that completely decays during a time when early LTP is normally consolidated to longer lasting LTP in wild-type animals. These observations correspond to severe deficits in hippocampus-dependent and -independent cognitive tasks, which require the consolidation of newly encoded memories (Plath et al., 2003). Our findings demonstrate central roles for activity-dependent genes in the establishment and maintenance of long-lasting changes in synaptic strength. We have now generated several knockout (KO) and Page artifical chromosome based transgenic animals that represent unique and ideal tools to further study the functional roles of activity dependent genes in synaptic plasticity.

Goals

We want to move from the identification of activity regulated genes to the analysis of LTP and assess which consequences they convey on the behavior of animals and their capability to learn and store memories. To this end, we continue to use a multi-disciplinary approach that includes (i) genomic and proteomic approaches, (ii) reverse genetic approaches in the animal and primary neuronal cultures, (iii) electrophysiological recordings from hippocampal neurons in vivo and in vitro, and (iv) analysis of acquisition and consolidation of memory traces using behavioural learning tasks. We anticipate that this analysis will provide insights into how expression of genes that are activated in coordinated biochemical pathways may contribute to the formation of synaptic plasticity. In as much as the identified genes bear the potential to act as direct effectors of neuronal function, they become promising targets for the therapeutic intervention of a variety of diseases that involve disturbances of synaptic plasticity.

Methods

Yeast-two- and tri-hybrid assays; affinity chromatography; co-immunoprecipitation; 2D-electrophoresis; expression profiling; Realtime PCR; modification of PACs by ET recombination; ES- cell culture; generation of tg and conditional ko mice; transfection of primary neuronal cultures; catFISH analysis; kinase-, promoter-, and neurite outgrowth assays; electrophysiology, behavioural analysis, including explicit and implicit learning tasks

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