• Charting Neurotypical Change in Complement and Cytokine Levels Across Postnatal Human Cortical Development

      Sager, Rachel (2021-12)
      A burgeoning body of evidence supports a role for immune signals in neurotypical human brain development. Furthermore, associations between neuroinflammation in development and the subsequent increased risk for psychiatric disorders indicate that an excess of immune signaling early in life damages brain function later in life. In this dissertation, I examined the postnatal expression of two major immune signaling families: complement and cytokines; and the relative contributions of neural cell types to the cortical transcriptome. I used high-throughput microarray, quantitative reverse transcription PCR, immunohistochemistry and multiplex immunoassays. I found coordinated increases in glial cell marker, complement, and cytokine transcripts from birth until the typical age of entry into school (age 5). There were two main patterns of change in gene expression encoding immune signals and their receptors: an early postnatal peak in toddlers followed by a decline in expression levels (C1Q, C3, IL-1β, CD11B, IL-1R1, IL-18) and an early postnatal increase in toddlers, followed by additional increases in adolescents and young adults (IL-6, TNF-α). Complement inhibitor mRNAs were also differentially expressed across postnatal human life, increasing before reaching a plateau around school age (CD46, CD55, CR1,) or peaking in young adulthood (SERPING1, CD59). This suggests sustained complement inhibition during adolescence. The multiple cytokine and complement family members that peaked in toddlers suggest a period of dominant immune signaling from age two to five in humans. This may be related to the proliferation or maturation of glia during early postnatal development, whereas the cytokines seen increasing in adolescents and young adults are contemporaneous with periods of proposed increases in synaptic elimination. These findings open up additional avenues of investigation into the role of immune signaling in normal mammalian brain development and support that time periods of normative increases in developmental immune factor signaling overlap with known 'windows of vulnerability' to manifesting autism and schizophrenia.