Protracted postnatal development of inhibitory synaptic transmission in rat hippocampal area CA1 neurons

In the CNS, inhibitory synaptic function undergoes profound transformation during early postnatal development. This is due to variations in the subuni t composition of subsynaptic GABA(A) receptors (GABA(A)Rs) at differing dev elopmental stages as well as other factors. These include changes in the dr iving force for chloride-mediated conductances as well as the quantity and/ or cleft lifetime of released neurotransmitter. The present study was under taken to investigate the nature and time course of developmental maturation of GABAergic synaptic function in hippocampal CA1 pyramidal neurons. In ne onatal [postnatal day (P) 1-7] and immature (P8-14) CA1 neurons, miniature inhibitory postsynaptic currents (mIPSCs) were significantly larger, were l ess frequent, and had slower kinetics compared with mIPSCs recorded in more mature neurons. Adult mIPSC kinetics were achieved by the third postnatal week in CA1 neurons. However, despite this apparent maturation of mIPSC kin etics, significant differences in modulation of mIPSCs by allosteric agonis ts in adolescent (P15-21) neurons were still evident. Diazepam (1-300 nM) a nd zolpidem (200 nM) increased the amplitude of mIPSCs in adolescent but no t adult neurons. Both drugs increased mIPSC decay times equally at both age s. These differential agonist effects on mIPSC amplitude suggest that in ad olescent CA1 neurons, inhibitory synapses operate differently than adult sy napses and function as if subsynaptic receptors are not fully occupied by q uantal release of GABA. Rapid agonist application experiments on perisomati c patches pulled from adolescent neurons provided additional support for th is hypothesis. In GABA(A)R currents recorded in these patches, benzodiazepi ne amplitude augmentation effects were evident only when nonsaturating GABA concentrations were applied. Furthermore nonstationary noise analysis of m IPSCs in P15-21 neurons revealed that zolpidem-induced mIPSC augmentation w as not due to an increase in single-channel conductance of subsynaptic GABA (A)Rs but rather to an increase in the number of open channels responding t o a single GABA quantum, further supporting the hypothesis that synaptic re ceptors may not be saturated during synaptic function in adolescent neurons . These data demonstrate that inhibitory synaptic transmission undergoes a markedly protracted postnatal maturation in rat CA1 pyramidal neurons. In t he first two postnatal weeks, mIPSCs are large in amplitude, are slow, and occur infrequently. By the third postnatal week, mIPSCs have matured kineti cally but retain distinct responses to modulatory drugs, possibly reflectin g continued immaturity in synaptic structure and function persisting throug h adolescence.