title: Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly.
abstract: BACKGROUND
  Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders.
  
  
  METHODS
  A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development.
  
  
  RESULTS
  Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults.
  
  
  CONCLUSIONS
  Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders.
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Aceti
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Creson
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida; Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vaissiere
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Advanced Imaging Core, National Institute on Deafness and Other Communication Disorders/National Institutes of Health, Bethesda, Maryland.
authors.forename: Ya-Xian
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Advanced Imaging Core, National Institute on Deafness and Other Communication Disorders/National Institutes of Health, Bethesda, Maryland.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Damon T
authors.initials: DT
authors.lastname: Page
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida; Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida. Electronic address: grumbaug@scripps.edu.
authors.forename: Gavin
authors.initials: G
authors.lastname: Rumbaugh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000254:growth & development*; D003213:Conditioning, Psychological / Q000502:physiology; D049229:Dendritic Spines / Q000473:pathology / Q000502:physiology; D058068:Endophenotypes; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D057895:Haploinsufficiency; D006624:Hippocampus / Q000002:abnormalities / Q000254:growth & development; D018782:Maze Learning / Q000502:physiology; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000002:abnormalities / Q000254:growth & development; D017966:Pyramidal Cells / Q000473:pathology / Q000502:physiology*; D012683:Sensory Deprivation / Q000502:physiology; D014738:Vibrissae / Q000502:physiology; D020703:ras GTPase-Activating Proteins / Q000172:deficiency* / Q000235:genetics*
chemical_list: C484512:Syngap1 protein, mouse; D020703:ras GTPase-Activating Proteins
keywords: Autism spectrum disorder; Development; Epilepsy; Intellectual disability; Mouse model; Synapse; Syngap1