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J. Biol. Chem., Vol. 281, Issue 39, 29076-29084, September 29, 2006

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Transgenic Mice Expressing Dominant-negative Activin Receptor IB in Forebrain Neurons Reveal Novel Functions of Activin at Glutamatergic Synapses^*

Mischa Roland Müller, Fang Zheng, Sabine Werner¹², and Christian Alzheimer¹³

From the Institute of Cell Biology, Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland and the Institute of Physiology, University of Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany

The transforming growth factor family member activin is an important regulator of development and tissue repair. It is strongly up-regulated after acute injury to the adult brain, and application of exogenous activin protects neurons in several lesion models. To explore the role of endogenous activin in the normal and acutely damaged brain, we generated transgenic mice expressing a dominant-negative activin receptor IB (dnActRIB) mutant in forebrain neurons. The functionality of the transgene was verified in vivo. Hippocampal neurons from dnActRIB mice were significantly more vulnerable to intracerebroventricular injection of the excitotoxin kainic acid than those from control littermates, indicating a crucial role of endogenous activin in the rescue of neurons from excitotoxic insult. Because dnActRIB is only expressed in neurons, but not in glial cells, activin affords protection at least in part through a direct action on endangered neurons. Unexpectedly, the transgenic mice also revealed a prominent novel role of activin in glutamatergic neurotransmission in the intact adult brain. Electrophysiologic examination of excitatory synapses onto CA1 pyramidal cells in hippocampal slices of dnActRIB mice showed a reduced NMDA current response, which was associated with impaired long term potentiation. This is the first demonstration that activin receptor signaling is essential to optimize the performance of neuronal circuits in the mature brain under physiological conditions.

Received for publication, May 23, 2006 , and in revised form, July 25, 2006.

^* This work was supported by the ETH Zurich, the Swiss National Science Foundation (Grant 3100A0-109340/1 (to S. W.)), the University of Kiel, and the Deutsche Forschungsgemeinschaft (SFB 391, TP A9 (to C. A.)). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Joint senior authors.

² To whom correspondence may be addressed: Institute of Cell Biology, ETH Zurich, Honggerberg, HPM D42, CH-8093 Zurich, Switzerland. E-mail: sabine.werner{at}cell.biol.ethz.ch. ³ To whom correspondence may be addressed: Institute of Physiology, University of Kiel, Olshausenstr. 40, D-24098 Kiel, Germany. E-mail: c.alzheimer{at}physiologie.uni-kiel.de.

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