FEBS Theodor Buecher Lecture

Ludwig-Maximilians-University, Munich, DE

Neuronal circuit dysfunction in Alzheimer's disease

The accumulation of amyloid‐beta in the brain is an essential feature of Alzheimer’s disease (AD).However, the impact of amyloid‐beta‐accumulation on neuronal dysfunction on the single cell level in vivo is poorly understood. The neurodegeneration observed in AD has been associated with synaptic dismantling and progressive decrease in neuronal activity. We tested this hypothesis in vivo by using two‐photon calcium imaging in the frontal cortex of a mouse model of AD. While a decrease in neuronal activity was indeed observed in a small group of cortical neurons, a substantial fraction of neurons exhibited an unexpected increase in the frequency of spontaneous calcium transients. These “hyperactive” neurons were found exclusively near the plaques of amyloid beta–depositing mice (Busche et al., Science, 2008). When analyzing the visual cortex, we found that a progressive deterioration of neuronal tuning for the orientation of visual stimuli occurred in parallel with an agedependent increase of the amyloid‐beta load (Grienberger et al., Nat. Comm, 2012). As in cortical neurons, there was a marked increase in the fractions of both silent and hyperactive neurons also in the plaque‐bearing CA1 region of the hippocampus of old transgenic mice (Busche et al., PNAS, 2012). However, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons already long before the formation of plaques, suggesting that soluble species of Abeta may underlie the impaired neuronal activity. In support of this model, we found that the acute treatment of transgenic mice with a gamma secretase inhibitor reduced soluble Abeta levels and rescued the neuronal dysfunction. Together, our results identify neuronal hyperactivity as a major cellular mechanism underlying circuit dysfunction in AD.

Biography

Arthur Konnerth is the Friedrich Schiedel Chair and Director of the Institute of Neuro-science at the Technical University Munich, Germany. He obtained an MD at the Lud-wig-Maximilians University Munich and was already early during his medical studies engaged in neurophysiological research at the Max Planck Institute of Psychiatry (now Max Planck Institute of Neurobiology) in Martinsried. After performing postdoctoral research at the University of Pennsylvania and the Marine Biological Laboratory Woods Hole in the USA, he returned to Germany to join the laboratory of Bert Sakmann at the Max Planck Institute of Biophysical Chemistry in Göttingen. Together with his colleagues he developed in this period the method of patch-clamp recordings from neurons in brain slices. Still at the MPI of Biophysical Chemistry, he became head of a research group and focused on studies of synaptic function and plasticity in central neurons. In 1992, he accepted the chair of physiology at the Saarland University, and was afterwards chair of physiology both at the TU and LMU Munich. Since 2005, he is at the Institute of Neuroscience at the TU Munich.

His current research is concentrated on a better understanding of the mecha-nisms underlying brain function in health and disease. His lab studies different types of neurons and circuits in the cortex, cerebellum and hippocampus, and uses a variety of techniques, including electrophysiology, molecular biology, optogenetics, behavioral analyses and high-resolution optical imaging. A major focus of the work is directed towards an exploration of behavior-determined synaptic signaling and dendritic inte-gration in neurons of defined circuits in vivo. Another focus of the lab is the exploration of the mechanisms underlying neuronal dysfunction in Alzheimer’s disease. He and his team pioneered in vivo two-photon imaging of cortical circuits with single cell resolution. More recently, they developed the LOTOS method of high-resolution two-photon imaging and used it for the first time functional mapping of dendritic spines in vivo.

Arthur Konnerth is a member of the German Academy of Sciences Leopoldina, the Academia Europaea and the Bavarian Academy of Sciences and Humanities. He has an honorary doctorate from the Medical University of Timisoara, Romania. He received several awards, including the Max Planck Research Award, the Gottfried Wilhelm Leibniz Award, Adolf Fick Award, the Feldberg Award and an ERC Advanced Grant. He is currently chair of an ERC evaluation panel.