Changing properties of GABA(A) receptor-mediated signaling during early neocortical development

Evidence from several brain regions suggests gamma-aminobutyric acid (GABA) can exert a trophic influence during development, expanding the role of th is amino acid beyond its function as an inhibitory neurotransmitter. Prolif erating precursor cells in the neocortical ventricular zone (VZ) express fu nctional GABA(A) receptors as do immature postmigratory neurons in the deve loping cortical plate (CP); however, GABA(A) receptor propel-ties in these distinct cell populations have not been compared. Using electrophysiologica l techniques in embryonic and early postnatal neocortex, we find that GABA( A) receptors expressed by VZ cells have a higher apparent affinity for GABA and an relatively insensitive to receptor desensitization compared with ne urons in the CP. GABA-induced current magnitude increases with maturation w ith the smallest responses found in recordings from precursor cells in the VZ. No evidence was found that GABA(A) receptors on VZ cells are activated synaptically, consistent with previous data suggesting that these receptors are activated in a paracrine fashion by nonsynaptically released ligand. A fter neurons are born and migrate to the CP, they begin to demonstrate spon taneous synaptic activity, the majority of which is GABA(A) mediated. These spontaneous GABA(A) postsynaptic currents (sPSCs) first were detected at e mbryonic day 18 (E18). Al birth, similar to 50% of recordings from cortical neurons demonstrated GABA(A)-mediated sPSCs, and this value increased with age. GABA(A)-mediated sPSCs were action potential dependent and arose from local GABAergic interneurons. GABA application could evoke action potentia l-dependent PSCs in neonatal cortical neurons, suggesting that during the f irst few postnatal days, GABA can act as an excitatory neurotransmitter. Fi nally, N-methyl-D-aspartate (NMDA)- but not non-NMDA-mediated sPSCs were al so present in early postnatal neurons. These events were not observed in ce lls voltage clamped at negative holding potentials (-60 to -70 mV) but were evident when the holding potential was set at positive values (+30 to +60 mV). Together these results provide evidence for the early maturation of GA BAergic communication in the neocortex and a functional change in GABA(A)-r eceptor properties between precursor cells and early postmitotic neurons. T he change in GABA(A)-receptor properties may reflect the shift from paracri ne to synaptic receptor activation.