Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders

Brain Behav Immun. 2015 Nov;50:249-258. doi: 10.1016/j.bbi.2015.07.022. Epub 2015 Jul 26.

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.

Keywords: Anti-inflammatory; Autism; Dendritic spines; Excitation; Inflammation; Inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Dendritic Spines / drug effects
  • Dendritic Spines / immunology*
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials
  • Female
  • Maternal-Fetal Exchange*
  • Mice
  • Mice, Inbred C57BL
  • Neurodevelopmental Disorders / etiology
  • Neurodevelopmental Disorders / immunology*
  • Neurons / drug effects
  • Neurons / immunology
  • Pregnancy
  • Pyridines / pharmacology
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / growth & development
  • Somatosensory Cortex / immunology
  • Synapses / drug effects
  • Synapses / immunology*

Substances

  • Anti-Inflammatory Agents
  • Pyridines
  • ibudilast