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The Journal of Neuroscience, March 22, 2006, 26(12):3245-3255; doi:10.1523/JNEUROSCI.5118-05.2006

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Development/Plasticity/Repair
Differential Dependence of Axo-Dendritic and Axo-Somatic GABAergic Synapses on GABA_A Receptors Containing the 1 Subunit in Purkinje Cells

Jean-Marc Fritschy,¹ Patrizia Panzanelli,² Jason E. Kralic,¹ Kaspar E. Vogt,¹ and Marco Sassoè-Pognetto^2,3

¹Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland, and ²Department of Anatomy, Pharmacology, and Forensic Medicine and ³Rita Levi Montalcini Center for Brain Repair, University of Turin, I-10126 Turin, Italy

Correspondence should be addressed to Dr. Jean-Marc Fritschy, Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH- 8057 Zurich, Switzerland. Email: fritschy{at}pharma.unizh.ch

Synapse formation and maintenance require extensive transsynaptic interactions involving multiple signal transduction pathways. In the cerebellum, Purkinje cells (PCs) receive GABAergic, axo-dendritic synapses from stellate cells and axo-somatic synapses from basket cells, both with GABA_A receptors containing the 1 subunit. Here, we investigated the effects of a targeted deletion of the 1 subunit gene on GABAergic synaptogenesis in PCs, using electrophysiology and immunoelectron microscopy. Whole-cell patch-clamp recordings in acute slices revealed that PCs from 1^0/0 mice lack spontaneous and evoked IPSCs, demonstrating that assembly of functional GABA_A receptors requires the 1 subunit. Ultrastructurally, stellate cell synapses on PC dendrites were reduced by 75%, whereas basket cell synapses on the soma were not affected, despite the lack of GABA_A-mediated synaptic transmission. Most strikingly, GABAergic terminals were retained in the molecular layer of adult 1^0/0 mice and formed heterologous synapses with PC spines characterized by a well differentiated asymmetric postsynaptic density. These synapses lacked presynaptic glutamatergic markers and postsynaptic AMPA-type glutamate receptors but contained 2-glutamate receptors. During postnatal development, initial steps of GABAergic synapse formation were qualitatively normal, and heterologous synapses appeared in parallel with maturation of dendritic spines. These results suggest that synapse formation in the cerebellum is governed by neurotransmitter-independent mechanisms. However, in the absence of GABA_A-mediated transmission, GABAergic terminals in the molecular layer apparently become responsive to synaptogenic signals from PC spines and form stable heterologous synapses. In contrast, maintenance of axo-somatic GABAergic synapses does not depend on functional GABA_A receptors, suggesting differential regulation in distinct subcellular compartments.

Key words: synaptogenesis; gene targeting; cerebellum; dendritic spine; parallel fiber; inhibitory transmission

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Received Dec. 1, 2005; revised Feb. 4, 2006; accepted Feb. 7, 2006.

Correspondence should be addressed to Dr. Jean-Marc Fritschy, Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH- 8057 Zurich, Switzerland. Email: fritschy{at}pharma.unizh.ch

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