title: Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1.
abstract: 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.
  
  
  
  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.
authors.affiliation: Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Kellie A
authors.initials: KA
authors.lastname: Park
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Adema
authors.identifier: 0000-0001-6653-8645
authors.initials: A
authors.lastname: Ribic
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 80539 Munich, Germany.
authors.forename: Fabian M
authors.initials: FM
authors.lastname: Laage Gaupp
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut 06520, and.
authors.forename: Daniel
authors.identifier: 0000-0002-6289-0817
authors.initials: D
authors.lastname: Coman
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut 06520, and.
authors.forename: Yuegao
authors.identifier: 0000-0002-8719-6741
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Chris G
authors.identifier: 0000-0002-6560-6535
authors.initials: CG
authors.lastname: Dulla
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut 06520, and Department of Biomedical Engineering, Yale University, School of Engineering and Applied Science, New Haven, Connecticut 06520.
authors.forename: Fahmeed
authors.initials: F
authors.lastname: Hyder
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, thomas.biederer@tufts.edu.
authors.forename: Thomas
authors.identifier: 0000-0003-0912-1514
authors.initials: T
authors.lastname: Biederer
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000166:cytology* / Q000000981:diagnostic imaging; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D003214:Conditioning, Classical / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008569:Memory Disorders / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D013569:Synapses / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
chemical_list: C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D018756:GABA Antagonists; D007136:Immunoglobulins; D010320:Parvalbumins; D011724:Pyridazines; C049853:gabazine
keywords: Cadm; SynCAM; hippocampus; interneuron; nectin-like; synapse