During the development of the cortex, synaptic connections are formed in neural networks via intrinsic signals and spontaneous neural activity. These networks are prepared for their function, but have to learn and refine them in so-called critical periods through experience. This changes in particular the connection pattern of glutamatergic synapses between principal neurons. In our working hypothesis these changes are mainly controlled by silent synapses. Silent synapses form opportunities of synaptic connections by anatomically connecting two neurons, but due to the lack of AMPA receptors, synaptic transmission is limited. Experience-dependent activation of these silent synapses during the critical period allows them to mature by incorporating AMPA receptors, thereby consolidating the synaptic connection. The lack of activation presumably leads to the elimination of the silent synapses, so that at the end of the critical period, the silent synapses are constructively incorporated into the neural network. We suspect that defects of these processes are the basis of psychiatric diseases.
Overarching goals
- Molecular mechanisms of signaling specificity in synaptic long-term plasticity
- Molecular and cellular mechanisms of developmental plasticity in the brain
- Synaptic pathomechanisms of psychiatric diseases
Selection of current projects
- The maturation of silent synapses is controlled by the signaling scaffold proteins of the PSD-95 protein family. These proteins connect glutamate receptors in the postsynapse with signaling proteins. Mutations of proteins of these complexes are associated with diseases such as autism, schizophrenia, depression and bipolar disorders. Using genetically modified mice, we investigate the function of these protein complexes in silent synapse maturation. For this purpose, we use patch-clamp electrophysiology of brain slices in which we analyze the consequences on synaptic function in so-called loss- and gain-of-function approaches. Furthermore, we correlate synaptic defects with sensory and behavioral defects to obtain causal links of neuronal network defects to brain function.
- Drugs induce silent synapses in the nucleus accumbens, a brain region that controls motivated behavior. This pharmacologically generates a juvenile synaptic pattern, which we postulate as the basis for the drug-induced behaviour. In mouse models, we analyze cocaine-induced synaptic changes using brain-slice electrophysiology and optogenetic methods to find possible starting points for therapeutic interventions.
- Fragments of amyloid precursor protein (APP) induce juvenile synaptic properties. APP is typically highly expressed during postnatal brain development. We hypothesize that the induced juvenile properties destabilize synapses and thus promote their loss. We investigate the role of APP and its fragments on developmental plasticity and synaptic function in old mice.
Scientific collaboration
External:
- Dr. Yan Dong (University of Pittsburgh)
- Dr. Weifeng Xu (MIT)
- Prof. Siegrid Löwel (Universität Göttingen)
- Prof. Moritz Rossner (LMU)
- Dr. Yanhua Huang (University of Pittsburgh Medical Center)
Internal:
- Dr. Hans Klafki (UMG)
- Prof. Oliver Wirths (UMG)
- Dr. Dilja Krüger-Burg (UMG/MPI für Experimentelle Medizin)
Awards/Funding
- SFB889/DFG: Interplay of excitatory silent synapses, inhibitory synapses and synapse pruning in critical period plasticity
- Schram Stiftung: Mechanisms of dendritic Kv inactivation to gate spike-timing-dependent synaptic potentiation
- Whitehall Foundation: Synaptic mechanisms governing visual cortex critical periods
- Alzheimer’s Association: Vulnerability of rejuvenated synapses in Alzheimer’s Disease
Contact
Research group leader
Prof. Dr. Dr. Oliver Marcus Schlüter
Tel.: +49 551 3965236
Tel.: +1 412-624-1876
oschlue(at)gwdg.de
schluter(at)pitt.edu
External association:
- Assistant Professor: Department of Neuroscience der Universität Pittsburgh, PA, USA