During postnatal development, sensory experiences play critical roles in the refinement of cortical connections. However, both the process of postnatal experience-dependent maturation of neocortical inhibitory networks and its underlying mechanisms remain elusive. Here, we examined the differential properties of intracortical inhibitory networks of layer IV in "sensory-spared" and "sensorydeprived" cortices of glutamate acid decarboxylase 67 (GAD67)-green fluorescent protein (GFP) (⌬neo) and wild-type mouse. Our results showed that row D whisker trimming (WT) begun at postnatal day 7 (P7), but not after P15, induced a robust reduction of parvalbumin (PV) expression, measured by the PV/GFP ratio and PV cell densities, in the deprived barrels. WT also induced a robust reduction in the number of inhibitory perisomatic varicosities and synaptic GAD65/67 immunoreactivities in spiny neurons of the deprived barrels. Although the GAD65/67 expressions in interneurons were also downregulated in the deprived barrels, the GFP expression remained unchanged. Patch-clamp recording from spiny cells showed a 1.5-fold reduction of intracortical evoked IPSCs (eIPSCs) in deprived versus spared cortices. The reduction in eIPSCs occurred via changes in presynaptic properties and unitary IPSC amplitudes. Miniature IPSCs showed subtle but significant differences between the two experimental conditions. In addition, properties of the IPSCs in deprived barrels resemble those of IPSCs recorded in immature brains (P7). Together, these results suggest that the properties of local intracortical inhibitory networks are modified by sensory experiences. Perisomatic inhibition mediated by PV-positive basket cells is pruned by sensory deprivation.

In adult cortices, the ratio of excitatory and inhibitory conductances (E/I ratio) is presumably balanced across a wide range of stimulus conditions. However, it is unknown how the E/I ratio is postnatally regulated, when the strength of synapses are rapidly changing. Yet, understanding of such a process is critically important, because there are numerous neuropsychological disorders, such as autism, epilepsy and schizophrenia, are associated with disturbed E/I balances. Here we directly measured the E/I ratio underlying locally induced synaptic conductances in principal neurons from postnatal day 8 through 60. We found that 1) within each developmental period, the E/I ratio across 4 major cortical layers was maintained at a similar value under wide range of stimulation intensities; and 2) there was a rapid developmental decrease in the E/I ratio, which occurred within a sensitive period between P8 to P18 with exception of layer II/III. By comparing the excitatory and inhibitory conductances, as well as key synaptic protein expressions, we found a net increase in the number and strength of inhibitory, but not excitatory synapses, is responsible for the developmental decrease in the E/I ratio in the barrel cortex. The inhibitory markers were intrinsically co-regulated, gave rise to a sharp increase in the inhibitory conductance from P8 to P18. These results suggest that the tightly regulated E/I ratios in adults cortex is a result of drastic changes in relative weight of inhibitory but not excitatory synapses during critical period, and the local inhibitory structural changes are the underpinning of altered E/I ratio across postnatal development.

Mechanisms underlying experience-dependent refinement of cortical connections, especially GABAergic inhibitory circuits, are unknown. By using a line of mutant mice that lack activity-dependent BDNF expression (bdnf-KIV), we show that experience regulation of cortical GABAergic network is mediated by activity-driven BDNF expression. Levels of endogenous BDNF protein in the barrel cortex are strongly regulated by sensory inputs from whiskers. There is a severe alteration of excitation and inhibition balance in the barrel cortex of bdnf-KIV mice as a result of reduced inhibitory but not excitatory conductance. Within the inhibitory circuits, the mutant barrel cortex exhibits significantly reduced levels of GABA release only from the parvalbumin-expressing fast-spiking (FS) interneurons, but not other interneuron subtypes. Postnatal deprivation of sensory inputs markedly decreased perisomatic inhibition selectively from FS cells in wild-type but not bdnf-KIV mice. These results suggest that postnatal experience, through activity-driven BDNF expression, controls cortical development by regulating FS cellmediated perisomatic inhibition in vivo.neurotrophin | plasticity | brain derived neurotrophic factor

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