Abstract
The prevalent use of antibiotics in pregnant women and neonates raises concerns about long-term risks for children’s health, but their effects on the central nervous system is not well understood. We studied the effects of perinatal penicillin exposure (PPE) on brain structure and function in mice with a therapeutically relevant regimen. We used a battery of behavioral tests to evaluate anxiety, working memory, and sensory processing, and immunohistochemistry to quantify changes in parvalbumin-expressing inhibitory interneurons (PV+ INs), perineuronal nets (PNNs), as well as microglia density and morphology. In addition, we performed mesoscale calcium imaging to study neural activity and functional connectivity across cortical regions, and two-photon imaging to monitor dendritic spine and microglial dynamics. We found that adolescent PPE mice have abnormal sensory processing, including impaired texture discrimination and altered prepulse inhibition. Such behavioral changes are associated with increased spontaneous neural activities in various cortical regions, and delayed maturation of PV+ INs in the somatosensory cortex. Furthermore, adolescent PPE mice have elevated elimination of dendritic spines on the apical dendrites of layer 5 pyramidal neurons, as well as increased ramifications and spatial coverage of cortical microglia. Finally, while synaptic defects are transient during adolescence, behavioral abnormalities persist into adulthood. Our study demonstrates that early-life exposure to antibiotics affects cortical development, leaving a lasting effect on brain functions.
Highlights
Antibiotics have revolutionized medicine and saved countless lives
We found that penicillin exposure (PPE) significantly increased sensorimotor gating and decreased the ability to discriminate between textures
To examine how PPE affects sensory processing, we gave penicillin (31 mg/kg bodyweight per day) to pregnant dams in their drinking water starting on embryonic day (E) 16 to postnatal day (P) 15 (Figure 1A)
Summary
Antibiotics have revolutionized medicine and saved countless lives. Over the past few decades, they have been extensively used in pediatric care in developing and developed countries alike (Rogawski et al, 2017; Youngster et al, 2017). Penicillin exposure in the second and third trimesters have been associated with an increased risk of autism spectrum disorder (ASD) (Atladottir et al, 2012). Corroborating these findings, rodents subjected to various antibiotic regimens have been found to exhibit a number of behavioral abnormalities, including decreased sociability (Desbonnet et al, 2014; Leclercq et al, 2017), increased anxiety-like behaviors (Tochitani et al, 2016), and increased visceral hypersensitivity (O’Mahony et al, 2014)
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