1. Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1.
- Author
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Park KA, Ribic A, Laage Gaupp FM, Coman D, Huang Y, Dulla CG, Hyder F, and Biederer T
- Subjects
- Animals, CA3 Region, Hippocampal diagnostic imaging, Cell Adhesion Molecule-1, Cell Adhesion Molecules genetics, Conditioning, Classical drug effects, Fear drug effects, Female, GABA Antagonists pharmacology, Gene Expression Regulation drug effects, Immunoglobulins genetics, In Vitro Techniques, Male, Memory Disorders diagnostic imaging, Memory Disorders genetics, Memory Disorders pathology, Memory Disorders physiopathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Neural Pathways drug effects, Parvalbumins metabolism, Pyridazines pharmacology, Synaptic Potentials drug effects, Synaptic Potentials genetics, Time Factors, CA3 Region, Hippocampal cytology, Cell Adhesion Molecules metabolism, Gene Expression Regulation genetics, Immunoglobulins metabolism, Neural Inhibition physiology, Neural Pathways physiology, Synapses physiology
- Abstract
Unlabelled: Select adhesion proteins control the development of synapses and modulate their structural and functional properties. Despite these important roles, the extent to which different synapse-organizing mechanisms act across brain regions to establish connectivity and regulate network properties is incompletely understood. Further, their functional roles in different neuronal populations remain to be defined. Here, we applied diffusion tensor imaging (DTI), a modality of magnetic resonance imaging (MRI), to map connectivity changes in knock-out (KO) mice lacking the synaptogenic cell adhesion protein SynCAM 1. This identified reduced fractional anisotropy in the hippocampal CA3 area in absence of SynCAM 1. In agreement, mossy fiber refinement in CA3 was impaired in SynCAM 1 KO mice. Mossy fibers make excitatory inputs onto postsynaptic specializations of CA3 pyramidal neurons termed thorny excrescences and these structures were smaller in the absence of SynCAM 1. However, the most prevalent targets of mossy fibers are GABAergic interneurons and SynCAM 1 loss unexpectedly reduced the number of excitatory terminals onto parvalbumin (PV)-positive interneurons in CA3. SynCAM 1 KO mice additionally exhibited lower postsynaptic GluA1 expression in these PV-positive interneurons. These synaptic imbalances in SynCAM 1 KO mice resulted in CA3 disinhibition, in agreement with reduced feedforward inhibition in this network in the absence of SynCAM 1-dependent excitatory drive onto interneurons. In turn, mice lacking SynCAM 1 were impaired in memory tasks involving CA3. Our results support that SynCAM 1 modulates excitatory mossy fiber inputs onto both interneurons and principal neurons in the hippocampal CA3 area to balance network excitability., Significance Statement: This study advances our understanding of synapse-organizing mechanisms on two levels. First, the data support that synaptogenic proteins guide connectivity and can function in distinct brain regions even if they are expressed broadly. Second, the results demonstrate that a synaptogenic process that controls excitatory inputs to both pyramidal neurons and interneurons can balance excitation and inhibition. Specifically, the study reveals that hippocampal CA3 connectivity is modulated by the synapse-organizing adhesion protein SynCAM 1 and identifies a novel, SynCAM 1-dependent mechanism that controls excitatory inputs onto parvalbumin-positive interneurons. This enables SynCAM 1 to regulate feedforward inhibition and set network excitability. Further, we show that diffusion tensor imaging is sensitive to these cellular refinements affecting neuronal connectivity., (Copyright © 2016 the authors 0270-6474/16/367465-12$15.00/0.)
- Published
- 2016
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