UC Santa Cruz

ABSTRACT

James Francis Perna III

Perinatal penicillin exposure affects cortical development and adolescent sensoryprocessing

BACKGROUND: Recent epidemiological and experimental work has raised concern thatthe use of antibiotics during early-life may have long-term detrimental consequences for children’s metabolic, immunological, and neuropsychological health. The effects of penicillin on the central nervous system (CNS) is not well understood. METHODS: We studied the effects of perinatal penicillin exposure (PPE) on brain structure and function in mice. Mice were maternally exposed to penicillin by administering a therapeutically relevant dose of penicillin to pregnant and nursing dams in their drinking water. We used a battery of behavioral tests to evaluate anxiety, working memory, and sensory processing at adolescence and immunohistochemistry to quantify changes in parvalbumin-expressing inhibitory interneurons (PV INs), perineuronal nets (PNNs), as well as microglia density, morphology, and dynamics. In addition, we used RT-qPCR and ELISA assays to examine systemic and cortical inflammatory states. Furthermore, we performed mesoscale Ca2+ in vivo imaging of awake adolescent mice to study neural activity and functional connectivity across cortical regions and two-photon in vivo imaging of sedated adolescent mice to monitor dendritic spine as well as microglial dynamics.

RESULTS: We found that PPE mice had altered sensory processing, including impairedtexture discrimination and augmented prepulse inhibition. These behavioral abnormalities were associated with decreased functional connectivity and increased neuronal activities across the cortex as well as within the somatosensory cortex. Furthermore, PPE mice showed delayed maturation of PV INs in the somatosensory cortex, as well as significantly lower density of dendritic spines on the apical dendrites of layer 5 pyramidal neurons therein driven by an increased elimination rate. Interestingly, while the density and baseline terminal tip dynamics of cortical microglia were not altered, their ramifications and spatial coverages were significantly increased in the PPE mouse brain, resulting in overlapping territories between neighboring microglia.

CONCLUSION: This work demonstrates that early-life penicillin exposure can disruptcortical development and neuronal circuit formation, leaving lasting effects on brain functions. More generally, it broadens our awareness of how the neurobiological and behavioral development of our children may be vulnerable to early-life antibiotic exposure. Furthermore, it offers insight into a potential mechanistic chain linking antibiotic exposure, microbiota perturbation, immunological signaling, neuronal development, and behavior as well as exploring the potential to exploit the gut-brain interaction to treat neurological and behavioral malfunctions, thus, helping to ensure that children exposed to antibiotics have the health and wellbeing to live free from disease or disability.