Description

The major focus of Prof. Konnerth’s group is currently the multi-photon imaging-based analysis of receptors and channels underlying the function of neural circuits in the brain of mammals ‘in vivo’ and ‘in vitro’ brain slices. The analysis focuses on the mechanisms of intracellular signal transduction cascades that regulate the experience-dependent regulation of gene expression. For this purpose we study, for example, the ‘in vivo’ function of NMDA receptors and voltage-gated Ca channels in dendritic spines, and we investigate the role of TRP channels for synaptic signalling and plasticity in Purkinje cells of the cerebellum (mouse model for TRP channels by the group of Biel). An important basis for these studies was our development of a new labelling technique of neuronal circuits with fluorescent Ca probes ‘in vivo’ in the mouse brain. This technique can be used in combination with targeted mutations in mice, thus allowing a much improved investigation of the molecular determinants of function in the intact brain of behaving mice. In particular, we are interested in understanding the mechanisms underlying the enormous plasticity of the immature brain. This high degree of plasticity is present during a relatively short period of development and decisively important for the fine structure of neural networks. The studies will reveal on the level of individual synaptic contacts (= dendritic spines) the modifications in structure and function produced by sensory experience (collaboration with the Bonhoeffer group). This high degree of precision requires the implementation of new probes, including genetically encoded, FRET-based indicators as well as the use of quantum dots. Preliminary studies that were performed in collaboration with Dr. Oliver Griesbeck, MPI of Neurobiology Martinsried, demonstrated the high potential of a new Troponin C-based FRET-probe for two-photon calcium imaging in the mouse brain.

 

The group of Prof. Hofmann is interested in the mechanisms of neural plasticity that involve the transcription of specific genes. The signalling mechanism from outside to the nucleus is known for some pathways, but not for most other pathways. The group could show that, depending on the brain area, the cGMP kinase I and/or the L-type Cav1.2 Ca2+ channel are involved in the modulation of neuronal plasticity (1–5). The mechanism by which cGMP kinase modulates presynaptic transmitter release (hippocampus) and/or postsynaptic excitation (cerebellum) is poorly understood. In contrast, activation of the Cav1.2 channel modulates apparently only postsynaptic adaptation. Surprisingly, the Cav1.3 channel also expressed in the hippocampus does not contribute to Cre-activation. The postulate is that either CaM or CaM kinase II trigger gene transcription, whereas the elevation of postsynaptic [Ca2+]i by itself has no effect on the transcription or L-LTP. Prof. Hofmann is planning to analyse this signalling pathway at the level of the intact mouse.

 

The group of Prof. Haass investigates how protein function and dysfunction is affected by a number of age related brain disorders. These specifically include Alzheimer's- and Parkinson's disease (AD/PD). Projects related to these are part of the SFB 596 "Molecular Mechanisms of Neurodegeneration". A strong focus is on the mechanisms leading to Amyloid ß-peptide generation and deposition. After setting the stage by showing that Amyloid ß-peptide is a physiologically occurring peptide, whose production can be studied in tissue culture systems (a finding, which primed the entire research in this field), the Haass laboratory is now consequently working on all three secretases (the amyloidogenic ß-, and -secretase and the non-amyloidogenic -secretase). Throughout the last decade the laboratory provided the basis for the understanding of the proteolytic generation of Aß and the effects of familial AD associated mutations. More recently, -secretase was identified as a high molecular weight complex. Using a sophisticated combination of in vivo reconstitution in yeast combined with biochemical purification and in vitro activity assays it was shown that -secretase is composed of four different subunits including presenilin (as the catalytic core), Aph-1, Pen-2, and Nicastrin. Cellular assembly was shown and novel assembly factors were discovered recently. Assembly includes the retention of unassembled -secretase subunits within the endoplasmic reticulum (ER). Retention signals were identified and it was shown that during assembly such retention signals are masked and as a consequence the fully assembled complex is released from the ER. Using in vivo imaging analysis targeting of fully assembled biologically active -secretase to the plasma membrane could be shown. This work disproved the dogma that Presenilin is only located within the ER and therefore not related to -secretase activity. Moreover, the Haass lab identified a novel protease active site within Presenilin, which defines it as a GxGD-Aspartyl protease. Very recently, they could demonstrate that identical active site domains are used by signal peptide peptidase and its homologues. Moreover, all GxGD proteases have a dual intramembrane cleavage in common. These findings led to introduction of completely novel class of proteases: the GxGD-type aspartyl proteases.

 

The group of Prof. Magdalena Götz (winner of the 2007 Leibniz-Price) investigates the transcriptional regulation of neural stem cell fate, in particular Pax6 as a key neurogenic determinant. The differentiation of neural stem cells into functional neurons is the key for any approach towards functional neuron replacement after acute or chronic injury of the brain. The Götz previous work has identified the key role of the transcription factor Pax6 for neurogenesis during development. Using viral vectors to examine cell-autonomous functions in the adult stem cell niche in vivo, they could show that Pax6 is both necessary and sufficient for neural stem cells to proceed towards neurogenesis. They could further show that Pax6 is also sufficient to instruct neurogenesis in the adult cerebral cortex after stab wound injury, a region of the adult brain where normally no adult neurogenesis occurs. These data therefore provide proof-of-principle evidence that Pax6 acts as a key neurogenic determinant sufficient to instruct neurogenesis from glial cells in the adult brain after injury. Close collaborations exist with the group of Bally-Cuif in regard to the molecular mechanisms allowing widespread neurogenesis in the adult zebrafish brain.

 

The group of Prof. Biel is interested in the role of cGMP/cAMP-regulated cation channels (CNG and HCN channels) in neuronal function. Using a combination of molecular biology techniques, electrophysiological methods and gene targeting in mice the group has elucidated the physiological relevance of two members of the CNG channel family in vision and olfaction. CNGA3 is crucial for cone photoreceptor function. Deletion of this protein induces total colorblindness in mouse and man. The CNGB1 subunit was shown by this group to cause retinitis pigmentosa (RP) and olfactory impairment. Total colorblindness and RP are associated with a progressive degeneration of cone and rod photoreceptors. The cellular signaling pathways underlying this pathological process are currently investigated by the group. Moreover, lentiviral vectors are developed by the group to functionally rescue the loss of CNG channels in CNGA3 and CNGB1 knockout mice and to study the targeting of these proteins in neurons. The second focus of the group is on HCN (pacemaker) channels. The group was among the first three labs to clone these channels. HCN channels control a variety of neuronal functions including determination of resting potential, neuronal pacemaking and dendritic integration. In the last few years the function and modulation of the four members of the HCN channel family (HCN1-4) was extensively investigated in this laboratory. In particular, mouse models were generated for this purpose.

 

Prof. Benedikt Grothe’s lab focuses on the mechanisms underlying information processing in the mammalian brain. They study temporal cues of acoustic stimuli that convey important information about the outer world. A critical question is what cellular mechanisms underlie precise spike timing which carries important information within the nervous system. Because of the unique relationship of structure and function in the auditory brainstem and because of the unsurpassed importance of temporal cues in auditory perception, auditory brainstem circuits are an ideal model system for studying various aspects of the processing of temporal information. A recent discovery in the lab was that inhibitory transmitters (e.g. glycine), transmitted with unexpected temporal precision, and therefore play a key role in processing temporal cues in the milli- and even microsecond range (e.g. in processing the difference in the time-of-arrival of a sound at the two ears, the chief cue to localize sounds in space). Moreover, inhibitory connections appear to be important for tuning single cells to the physiological range of temporal cues and to re-adjust the neural circuits in question, depending on the auditory environment (e.g. in strong background noise). Such experience dependent plasticity was unexpected in a neuronal circuit thought to operate in a rather static way. Currently the lab investigates how changes in precise spike-timing due to changes in ion-channel distributions can alter the way these circuits process information and how changes in receptor trafficking can explain short- and long-term adaptation of the auditory system to different acoustic environment.

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Campus Movie 2012

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TU München
MPG
Helmholtz München
MPI of Neurobiology
MPI of Biochemistry