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Although previous studies have explored the role of inhibition in regulating UDSs, little is known about whether this role changes with maturation. This is surprising since both slow oscillations and UDSs exhibit significant age\u2010dependent alterations. To elucidate the developmental impact of GABA<jats:sub>B<\/jats:sub> and GABA<jats:sub>A<\/jats:sub> receptors on UDS activity, we conducted simultaneous local field potentials and intracellular recordings <jats:italic>ex vivo<\/jats:italic>, in brain slices of young and adult male mice, using selective blockers, CGP55845 and a non\u2010saturating concentration of gabazine, respectively. Blockade of both GABA<jats:sub>B<\/jats:sub> and GABA<jats:sub>A<\/jats:sub> signalling showed age\u2010differentiated functions. CGP55845 caused an increase in Down state duration in young animals, but a decrease in adults. Gabazine evoked spike and wave discharges in both ages; however, while young networks became completely epileptic, adults maintained the ability to generate UDSs. Furthermore, voltage clamp recordings of miniature inhibitory postsynaptic currents revealed that gabazine selectively blocks phasic currents, particularly involving postsynaptic mechanisms. The latter exhibit clear maturational changes, suggesting a different subunit composition of GABA<jats:sub>A<\/jats:sub> receptors in young <jats:italic>vs<\/jats:italic>. adult animals. Indeed, subsequent local field potential recordings under diazepam (nanomolar or micromolar concentrations) revealed that mechanisms engaging the drug's classical binding site, mediated by \u03b11\u2010subunit\u2010containing GABA<jats:sub>A<\/jats:sub> receptors, make a bigger contribution to Up state initiation in young networks compared to adults. Taken together, these findings help clarify the mechanisms that underlie the maturation of cortical network activity and enhance our understanding regarding the emergence of neurodevelopmental disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Slow oscillations, the EEG hallmark of non\u2010REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered the default activity of the cerebral cortex and reflect the underlying neural connectivity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>GABA<jats:sub>B<\/jats:sub>\u2010 and GABA<jats:sub>A<\/jats:sub>\u2010receptor\u2010mediated inhibition play a major role in regulating UDS activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Although slow oscillations and UDSs exhibit significant alterations as a function of age, it is unknown how developmental changes in inhibition contribute to the developmental profile of this activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In this study, we reveal for the first time age\u2010dependent effects of GABA<jats:sub>B<\/jats:sub> and GABA<jats:sub>A<\/jats:sub> signalling on UDSs. We also document the differential subunit composition of postsynaptic GABA<jats:sub>A<\/jats:sub> receptors in young and adult animals, highlighting the \u03b11\u2010subunit as a major component of the age\u2010differentiated regulation of UDSs.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings help clarify the mechanisms that underlie the maturation of cortical network activity, and enhance our understanding regarding the emergence of neurodevelopmental disorders.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282736","type":"journal-article","created":{"date-parts":[[2022,4,2]],"date-time":"2022-04-02T04:48:48Z","timestamp":1648874928000},"page":"2401-2427","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["GABA<sub>B<\/sub>\u2010 and GABA<sub>A<\/sub>\u2010receptor\u2010mediated regulation of Up and Down states across 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