title: Mutation of the Dyslexia-Associated Gene Dcdc2 Enhances Glutamatergic Synaptic Transmission Between Layer 4 Neurons in Mouse Neocortex.
abstract: Variants in DCDC2 have been associated with reading disability in humans, and targeted mutation of Dcdc2 in mice causes impairments in both learning and sensory processing. In this study, we sought to determine whether Dcdc2 mutation affects functional synaptic circuitry in neocortex. We found mutation in Dcdc2 resulted in elevated spontaneous and evoked glutamate release from neurons in somatosensory cortex. The probability of release was decreased to wild-type level by acute application of N-methyl-d-aspartate receptor (NMDAR) antagonists when postsynaptic NMDARs were blocked by intracellular MK-801, and could not be explained by elevated ambient glutamate, suggesting altered, nonpostsynaptic NMDAR activation in the mutants. In addition, we determined that the increased excitatory transmission was present at layer 4-layer 4 but not thalamocortical connections in Dcdc2 mutants, and larger evoked synaptic release appeared to enhance the NMDAR-mediated effect. These results demonstrate an NMDAR activation-gated, increased functional excitatory connectivity between layer 4 lateral connections in somatosensory neocortex of the mutants, providing support for potential changes in cortical connectivity and activation resulting from mutation of dyslexia candidate gene Dcdc2.
authors.affiliation: Department of Physiology and Neurobiology.|Current address: Weill Cornell Medical College, Brain & Mind Research Institute, New York, NY 10021, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Che
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, CT 06269, USA.|Current address: Department of Pediatrics, Yale University, New Haven, CT 06520, USA.
authors.forename: Dongnhu T
authors.initials: DT
authors.lastname: Truong
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: R Holly
authors.initials: RH
authors.lastname: Fitch
authors.affiliation: Department of Physiology and Neurobiology.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: LoTurco
mesh_terms: D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D019579:Neocortex / Q000502:physiology*; D009415:Nerve Net / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D013003:Somatosensory Cortex / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: C570668:DCDC2 protein, mouse; D008869:Microtubule-Associated Proteins; D018377:Neurotransmitter Agents; D018698:Glutamic Acid
keywords: NMDA receptor; glutamate release; paired recording; presynaptic; reading disability