Backround and significance

Our project deals with diseases of the nervous system from a perspective of pathological synaptic communication. We will focus on altered neuronal communication in four important model disorders: schizophrenia, autism-spectrum disorders, mental retardation, chronic pain. We believe that all of these conditions have one common feature: a disturbed interplay between sensory processing and motor activity. We will therefore study sensory-motor integration, combining the molecular, cellular, network and behavioural level. Key questions are:

 

- How do neurons integrate afferent information and “translate” it into predictable outputs?

- Which structural and functional determinants alter coherent activity patterns in sensorimotor networks?

- How do perturbed synaptic and network-level communications result in pathological behaviour?

 

We are only beginning to unravel the causal links between these different scales, but new techniques and model systems together with innovative concepts will further our understanding. Upwards and downwards causality between the molecular, cellular, network and systems  level will be key for delineating the pathophysiology of complex neuro-psychiatric diseases. We focus on 4 paradigmatic disorders: schizophrenia, autism-spectrum disorders, mental retardation and chronic pain. While these conditions cover distinct changes in synaptic interactions, they all involve mutually dependent alterations at the synaptic, network and systems level. Sensorimotor gating, i.e. regulation of motor output by sensory input, and modulation of sensory stimulus processing by motor actions, is the unifying focus. It is altered in all disorders mentioned above, starting with elementary peripheral mechanisms in chronic pain, up to high78 er-level dysfunctions in complex psychiatric conditions.

 

Thus, it provides an ideal readout, which can be studied in parallel approaches using model organisms and humans. Integrated neuro-psychiatric projects are presently funded by the DFG, European research programs (EUsynapse, synsys) and multi-center European graduate school initiatives (EURON and SYNERGY). However, none of these programs covers the selected disorders from asynaptic dysfunction perspective – an approach for which Heidelberg is ideally prepared. We combine a long-standing tradition in molecular and cellular neurosciences with powerful clinical research, including the Central Institute of Mental Health (ZI), one of Europe‘s leading institutions in psychiatric neuroscience. Neuroscientists in Heidelberg and at the ZI are already closely linked within CellNetworks, the SFB 636 (coordinator Flor), and the BCCN. The project directly derives from the present neuroscience program of CellNetworks, integrating developmental and systems neurobiology. The focus on structure-function relationship has been further strengthened by the NIC and the appointment of Schröder, who studies synaptic ultrastructure. Most importantly, CellNetworks has been instrumental in joining together researchers from different system levels. These links between molecular-cellular, developmental and systems neuroscience will be exploited and further strengthened, making Heidelberg a unique place for translational research in neuro-psychiatric diseases.