title: Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders.
abstract: Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment.
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Pierluca
authors.initials: P
authors.lastname: Coiro
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Ragunathan
authors.initials: R
authors.lastname: Padmashri
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Suresh
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Spartz
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Gurudutt
authors.initials: G
authors.lastname: Pendyala
authors.affiliation: Department of Psychology, University of Nebraska - Lincoln, Lincoln, NE 68588, USA.
authors.forename: Shinnyi
authors.initials: S
authors.lastname: Chou
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Yoosun
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Brittney
authors.initials: B
authors.lastname: Meays
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Shreya
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Yazen
authors.initials: Y
authors.lastname: Alnouti
authors.affiliation: Department of Psychology, University of Nebraska - Lincoln, Lincoln, NE 68588, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: adunaevsky@unmc.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Dunaevsky
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D049229:Dendritic Spines / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D008431:Maternal-Fetal Exchange; D051379:Mice; D008810:Mice, Inbred C57BL; D065886:Neurodevelopmental Disorders / Q000209:etiology / Q000276:immunology*; D009474:Neurons / Q000187:drug effects / Q000276:immunology; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology; D013003:Somatosensory Cortex / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D013569:Synapses / Q000187:drug effects / Q000276:immunology*; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D000893:Anti-Inflammatory Agents; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles
keywords: Anti-inflammatory; Autism; Dendritic spines; Excitation; Inflammation; Inhibition