Over the last years our team has worked to study memory mechanisms at multiple levels of nervous system function. We carefully established behavioural paradigms to study different phases of memory formation and memory management, and employed high resolution gene expression analysis in order to identify gene products activated in these particular memory stages. Using genetic models we tested the relevance of identified molecular factors for different aspects of memory formation and underlying morphological changes in vivo. With our co-operation partners we were indeed able to identify neural activity patterns that are critical for memory storage and sensitive to manipulation of these gene products. To complement this systems level approach, we investigated the cellular functions mediated by the identified gene products and involved intracellular signalling networks in cell culture systems. Ultimately, we believe that this approach will allow us to link network activity patterns and intracellular signalling pathways during memory consolidation.
Adding to our range of approaches, we also maintain a fully equipped S2 level cell culture to investigate physiological mechanisms in a variety of neuronal and non-neuronal cellular model systems as well as in primary neuronal cultures of cortical and hippocampal origin. Aside from standard transfection, we also apply viral transduction to assess morphological changes, signaling pathway activity, and alteration in gene expression as well as as protein levels, using a variety of state-of-the-art methods.
A major part of our attention has been focussed on GABAergic local circuitry neurons, which are shaped by a combination of genetic (e.g., cell lineage, genetic imprinting), developmental (e.g., sex differentiation, juvenile stress) and environmental (sensory input) factors. A remarkable variability of these cells exists in respect to their morphological, physiological and neurochemical characteristics and in their ability to alter these features and thereby determine the responsiveness of the local network to various kinds of excitatory, inhibitory, and neuromodulatory input. We could indeed demonstrate the critical importance of these neurons for specific aspects of classical (“Pavlovian”) fear conditioning, such memory generalisation, extinction and cue/context balance. Virus-mediated gene transfer has been established in our lab to tackle the function of specific interneuron populations in vivo, controlling their activity with DREADD receptors and controlling the expression of specific molecular components by shRNA-mediated knock down. We currently further investigate GABAergic functions in relation to aversive and appetitive motivation (SFB779) and the development of psychiatric disorders.
On the other hand, to obtain a more comprehensive picture of the processes in the brain areas involved, we have begun to study gene products involved in excitatory neuron plasticity. We have identified the serine/threonine kinase Ndr2 as an inducible modulator of the actin cytoskeleton and determined memory consolidation phases sensitive to actin filament arrest. We have been able to dissect the mechanisms of Ndr2 action in the integrin-dependent differentiation of hippocampal neurons and are currently studying its role in synaptic plasticity and learning.
We furthermore apply our knowledge to genetic models of disease, specifically, the fragile X syndrome and the fragile X tremor and ataxia syndrome (Cure-FXTAS).