Prof. Dr. Johannes Vogt

Center of Anatomy, University Hospital of Cologne


Prof. Dr. Johannes Vogt
Prinicipal Investigator CECAD Cologne
 +49 221 478-5709

Uniklinik Köln
Zentrum Anatomie
Dept. of Molecular and Translational Neurosciences

50924 Köln

Johannes Vogt´s group works on synaptic lipid signaling, which regulates glutamatergic transmission and thereby cortical network excitability. While at young adult ages lipid-mediated cortical hyperexcitability is associated with psychiatric and food intake disorders, in aged individuals it seems to be involved in metabolic alteration, age-related cortical hyperexcitability and premature brain aging. Since altered metabolic conditions and a decline of cognitive abilities are common findings in an increasing portion of the aging population, we aim at understanding lipid-signaling mediated body-brain effects and their importance for metabolic and age-related disorders.

Our research: Metabolic changes affect bioactive lipid levels and thereby also synaptic lipid signaling, which may lead to cortical hyperexcitability, a typical finding in aging brains. We are therefore interested in elucidating the mutual connection of synaptic lipid signaling, metabolic regulation, aging and cognitive functions.

We identified a group of molecules regulating synaptic lipid signaling called plasticity-related genes (PRG´s/LPPRs), which regulate glutamatergic transmission in the cortex and thereby cortical network activity. Using different transgenic animal models, we dissected synaptic lipid signaling and analyzed associated behavioral phenotypes. Here, we found pathophysiologic synaptic lipid signaling to be involved in animal models for psychiatric disorders as well as to play a role in food intake control and metabolic disorders. Moreover, we have shown that a human PRG-1 SNP was associated with reduced cortical gating, an endophenotype of psychiatric disorders, as well as with metabolic alterations including BMI-increase and higher DMT2 prevalence. Using transgenic animals we could find a clear relationship between metabolic changes, cortical hyperexcitability and food intake, which could be modulated by genetic and pharmacological intervention.

Our goals: Our goals are to determine molecular pathways, which arise from the interplay of disrupted synaptic lipid signaling, cortical network hyperexcitability, metabolic alterations, and aging. Our data suggest that these conditions are part of a vicious circle leading to pathological metabolic conditions (obesity, DMT2) and premature brain aging. Since obesity is a major risk factor for Alzheimer`s disease (AD) and cortical network excitability a typical finding in AD, our data showing direct impact of synaptic lipid signaling on age-related cortical excitability and cognitive decline suggest a close association between bioactive lipids signaling in the brain and premature aging. We hereby follow a translational approach eventually aiming for therapeutic interventions for successful aging.

Our successes: Recently, we unraveled the importance of synaptic lipid signaling at excitatory cortical synapses and described the role of synaptic lipids in homeostatic regulation of glutamatergic transmission in the cortex (see schematic overview). While this pathway in adult animals regulates cortical excitability and on the behavioral level exploratory behavior and food intake, our latest findings suggest that in aged animals this pathway leads to age-related cortical hyperexcitability and premature brain aging. In line, disruption of this pathway prevented age-related cortical hyperexcitability and preserved cognitive function in aging animals when compared to their wild type litters. The synaptic lipid signaling pathway involves lipid level regulating molecules (Plasticity-related gene 1, PRG-1) in the postsynaptic compartment and competing LPA signaling partners in the presynaptic compartment (LPA-receptor 2; LPAR-2), both of which, affecting release probability of presynaptic glutamate vesicles. Loss of this regulation enhanced excitatory transmission leading to disrupted synaptic homeostasis and to cortical network hyperactivity. In a translational approach, we identified a human SNP in the PRG-1 gene (PRG-1R345T) and could show in comparable experiments in transgenic mice (expressing this mutation) and in human mutation carriers that resulting cortical network hyperexcitability led to reduced sensory gating, an endophenotype of psychiatric disorders typically present in Schizophrenia patients. We further showed that inhibiting synaptic lipid synthesis (executed in astrocytic processes at excitatory synapses) was an effective therapy for rescuing the observed endophenotype of schizophrenia and redirecting cortical hyperexcitability to normal values. This therapeutic intervention has a curative potential for CNS disorders related to cortical hyperexcitability and is the topic of a pending patent (WO201707199A1).

Our methods/techniques: Prof. Vogt´s group follows a molecular translational approach, which extends from the analysis of molecular signaling pathways in hetereologous systems and in transgenic mouse models up to systemic analyses in humans. We use molecular biological, cell biological and electrophysiological methods to modulate cortical circuits and to examine resulting behavioral phenotypes and metabolic processes in the brain. This translational approach aims at developing novel therapeutic approaches for human brain disorders associated with cortical hyperexcitability like psychiatric disorders but also metabolic disorders and age-related cognitive changes.


Figure 1: Schematic overview on synaptic lipid signaling at cortical synapses.

Homeostasis (left): the tripartite synapse, which contains the presynaptic compartment, the postsynaptic compartment and the astrocytic processes is the site of lysophosphatidic acid (LPA) signaling. LPA is synthetized by autotaxin (ATX), which is located in astrocytic processes. LPA produced at the synapse activates LPAR-2s located in the presynaptic compartment, where they modulate glutamate-vesicle release by Ca2+-signaling. PRG-1 is a LPA-interacting molecule, which regulates LPA-levels in the synaptic cleft by internalization into intracellular compartments.

Allostasis (right): disruption of postsynaptic PRG-1 function (e.g. by human SNPs) or metabolic changes affecting brain levels of LPA-precursors result in cortical network excitability and related disorders. Targeting LPA-synthesis by ATX inhibition, results in normalization of cortical excitability and rescue of hyperexcitability-related behavioral phenotypes.