Modulation of postsynaptic AMPA receptors in the brain by phosphorylation may play a role in the expression of synaptic plasticity at central excitatory synapses. It is known from biochemical studies that GluR1 AMPA receptor subunits can be phosphorylated within their C terminal by cAMP-dependent protein kinase A (PKA), which is colocalized with the phosphatase calcineurin (i.e., phosphatase 2B). We have examined the effect of PKA and calcineurin on the time course, peak open probability (P O,PEAK ), and single-channel properties of glutamateevoked responses for neuronal AMPA receptors and homomeric GluR1(flip) receptors recorded in outside-out patches. Inclusion of purified catalytic subunit C␣-PKA in the pipette solution increased neuronal AMPA receptor P O,PEAK (0.92) compared with recordings made with calcineurin included in the pipette (P O,PEAK 0.39). Similarly, C␣-PKA increased P O,PEAK for recombinant GluR1 receptors (0.78) compared with patches excised from cells cotransfected with a cDNA encoding the PKA peptide inhibitor PKI (P O,PEAK 0.50) or patches with calcineurin included in the pipette (P O,PEAK 0.42). Neither PKA nor calcineurin altered the amplitude of single-channel subconductance levels, weighted mean unitary current, mean channel open period, burst length, or macroscopic response waveform for recombinant GluR1 receptors. Substitution of an amino acid at the PKA phosphorylation site (S845A) on GluR1 eliminated the PKA-induced increase in P O,PEAK , whereas the mutation of a Ca 2ϩ ,calmodulin-dependent kinase II and PKC phosphorylation site (S831A) was without effect. These results suggest that AMPA receptor peak response open probability can be increased by PKA through phosphorylation of GluR1 Ser845. Key words: AMPA receptors; glutamate; LTD; PKA; calcineurin; open probability; GluR1Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the mammalian CNS. These glutamate receptors can be subdivided on the basis of agonist pharmacology and sequence homology into three classes, which include N-methyl-D-aspartate, kainate, and AM PA receptors. AM PA receptors mediate fast synaptic current at most excitatory synapses and are tetrameric or pentameric complexes assembled from any of four different subunits (GluR1-4) with variable stoichiometry (Hollmann and Heinemann, 1994;Dingledine et al., 1999).The modulation of excitatory synaptic transmission during long-term potentiation (LTP) and long-term depression (LTD), two well established cellular models of learning and memory, results from changes in the presynaptic release of glutamate and/or changes in postsynaptic glutamate receptor f unction or localization (

The developmental increase in the strength of inhibitory synaptic circuits defines the time window of the critical period for plasticity in sensory cortices. Conceptually, plasticity of inhibitory synapses is an attractive mechanism to allow for homeostatic adaptation to the sensory environment. However, a brief duration of visual deprivation that causes maximal change in excitatory synapses produces minimal change in inhibitory synaptic transmission. Here we examined developmental and experience-dependent changes in inhibition by measuring miniature IPSCs (mIPSCs) in layer 2/3 pyramidal neurons of mouse visual cortex. During development from postnatal day 21 (P21) to P35, GABA A receptor function changed from fewer higher-conductance channels to more numerous lower-conductance channels without altering the average mIPSC amplitude. Although a week of visual deprivation did not alter the average mIPSC amplitude, a subsequent 2 h exposure to light produced a rapid rebound potentiation. This form of plasticity is restricted to a critical period before the developmental change in GABAergic synaptic properties is completed, and hence is absent by P35. Visual experiencedependent rebound potentiation of mIPSCs is accompanied by an increase in the open channel number and requires activity-dependent transcription of brain-derived neurotrophic factor (BDNF). Mice lacking BDNF transcription through promoter IV did not show developmental changes in inhibition and lacked rebound potentiation. Our results suggest that sensory experience may have distinct functional consequences in normal versus deprived sensory cortices, and that experience-dependent BDNF expression controls the plasticity of inhibitory synaptic transmission particularly when recovering vision during the critical period.