Perinatal Penicillin Exposure Affects Cortical Development and Sensory Processing

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.

Maternal antibiotics disrupt microbiome, behavior, and temperature regulation in unexposed infant mice

“…This study adds to a rapidly growing literature demonstrating that ABx treatment can lead to significant shifts in behavior in rodent models, whether exposure occurs in early life (e.g., Leclercq et al., 2017; Perna et al., 2021; Tochitani et al., 2016) or adulthood (e.g., Ceylani et al., 2018; Desbonnet et al., 2015; Gacias et al., 2016; Sylvia et al., 2017). We also demonstrated, for the first time, that maternal ABx treatment can significantly impact thermoregulation in unexposed offspring.…”

“…Several additional studies have reported changes in patterns of gene expression in brain (Champagne-Jorgensen et al, 2020;Kayyal et al, 2020;Volkova et al, 2021), changes in microglia and other aspects of neural development (Perna et al, 2021), and/or sex-dependent alterations in behavior (e.g., anxiety, sensorimotor gating, sociability; Champagne-Jorgensen et al, 2020;Kayyal et al, 2020;Perna et al, 2021) in offspring following exposure of dams to ABx.…”

“…In addition, significant increases in both vasopressin 1B receptor (Avpr1b) and inflammatory cytokine (IL‐6, IL‐10, and Cxcl15) expression in the frontal cortex were found in ABx‐treated mice (Leclercq et al., 2017). Several additional studies have reported changes in patterns of gene expression in brain (Champagne‐Jorgensen et al., 2020; Kayyal et al., 2020; Volkova et al., 2021), changes in microglia and other aspects of neural development (Perna et al., 2021), and/or sex‐dependent alterations in behavior (e.g., anxiety, sensorimotor gating, sociability; Champagne‐Jorgensen et al., 2020; Kayyal et al., 2020; Perna et al., 2021) in offspring following exposure of dams to ABx.…”

Exposure to Antibiotics and Neurodevelopmental Disorders: Could Probiotics Modulate the Gut–Brain Axis?

“…Dysbiosis in mice can be obtained by exposing young animals to a cocktail of a broad spectrum of antibiotics that cause gut inflammation, depressive-like symptoms, social behavior and cognitive deficits, along with changes in brain neuronal firing and microglial–glial activation [ 178 ]. A recent study shows that perinatal exposure to antibiotics affects cortical development with a long-lasting effect on brain functions in young mice [ 184 ]. Perinatal penicillin exposure significantly increased sensorimotor gating and decreased the ability to discriminate between textures in adolescent mice.…”

“…Perinatal penicillin exposure significantly increased sensorimotor gating and decreased the ability to discriminate between textures in adolescent mice. These behavioral alterations were accompanied by increased spontaneous neuronal activities and a delayed maturation of inhibitory neuronal circuits [ 184 ]. An excess use of antibiotics induced neurotoxic effects on mice brain [ 185 ].…”