A developmental increase of inhibition promotes the emergence of hippocampal ripples.

Sharp wave-ripples (SPW-Rs) are a hippocampal network phenomenon critical for memory consolidation and planning. SPW-Rs have been extensively studied in the adult brain, yet their developmental trajectory is poorly understood. While SPWs have been recorded in rodents shortly after birth, the time point and mechanisms of ripple emergence are still unclear. Here, we combine in vivo electrophysiology with optogenetics and chemogenetics in 4 to 12-day-old mice to address this knowledge gap. We show that ripples are robustly detected and induced by light stimulation of channelrhodopsin-2-transfected CA1 pyramidal neurons only from postnatal day 10 onwards. Leveraging a spiking neural network model, we mechanistically link the maturation of inhibition and ripple emergence. We corroborate these findings by reducing ripple rate upon chemogenetic silencing of CA1 interneurons. Finally, we show that early SPW-Rs elicit a more robust prefrontal cortex response than SPWs lacking ripples. Thus, development of inhibition promotes ripples emergence.

Reorganization of adolescent prefrontal cortex circuitry is required for mouse cognitive maturation.

Most cognitive functions involving the prefrontal cortex emerge during late development. Increasing evidence links this delayed maturation to the protracted timeline of prefrontal development, which likely does not reach full maturity before the end of adolescence. However, the underlying mechanisms that drive the emergence and fine-tuning of cognitive abilities during adolescence, caused by circuit wiring, are still unknown. Here, we continuously monitored prefrontal activity throughout the postnatal development of mice and showed that an initial activity increase was interrupted by an extensive microglia-mediated breakdown of activity, followed by the rewiring of circuit elements to achieve adult-like patterns and synchrony. Interfering with these processes during adolescence, but not adulthood, led to a long-lasting microglia-induced disruption of prefrontal activity and neuronal morphology and decreased cognitive abilities. These results identified a nonlinear reorganization of prefrontal circuits during adolescence and revealed its importance for adult network function and cognitive processing.