Near coincidental pre- and postsynaptic action potentials induce associative long-term potentiation (LTP) or long-term depression (LTD), depending on the order of their timing. Here, we show that in visual cortex the rules of this spike-timing-dependent plasticity are not rigid, but shaped by neuromodulator receptors coupled to adenylyl cyclase (AC) and phospholipase C (PLC) signaling cascades. Activation of the AC and PLC cascades results in phosphorylation of postsynaptic glutamate receptors at sites that serve as specific "tags" for LTP and LTD. As a consequence, the outcome (i.e., whether LTP or LTD) of a given pattern of pre- and postsynaptic firing depends not only on the order of the timing, but also on the relative activation of neuromodulator receptors coupled to AC and PLC. These findings indicate that cholinergic and adrenergic neuromodulation associated with the behavioral state of the animal can control the gating and the polarity of cortical plasticity.

Several recent studies have demonstrated that the metabolism of energy substrates takes place in multiple compartments in both astrocytes and synaptic terminals from brain. There are a number of differences in the metabolism of astrocytes and synaptic terminals primarily due to the localization of key enzymes such as pyruvate carboxylase and glutamine synthetase in astrocytes. The present study determined the rates of ¹⁴CO₂ production from several energy substrates by primary cultures of astrocytes and cortical synaptic terminals from rat brain. The rates of ¹⁴CO₂ production from labelled substrates by astrocytes were 0.96 ± 0.13, 11.13 ± 0.67, 10.51 ± 0.35, 24.92 ± 1.66 and 4.80 ± 0.50 for D-[6-¹⁴C]gIucose, L-[U-¹⁴C]lactate, D-3-hydroxy[3-¹⁴C]butyrate, L-[U-¹⁴C]gIutamine and L-[U-¹⁴C]ma-late, respectively. The rates of ¹⁴CO₂ production were also measured in the presence of 5 mM aminooxyacetate (AOAA) to determine the effect of inhibiting the malate-aspartate shuttle and other transaminase reactions on the oxidation of energy substrates. In astrocytes the addition of AOAA decreased the rate of glutamine oxidation 5-fold, consistent with other studies showing that glutamine enters the TCA cycle via transamination. AOAA increased the rate of ¹⁴CO₂ production from labelled glucose 4-fold, suggesting that inhibition of alanine biosynthesis profoundly alters the utilization of glucose by astrocytes. AOAA also increased the oxidation of lactate and 3-hydroxybutyrate 36 and 58%, respectively. The rates of ¹⁴CO₂ production from labelled substrates by synaptic terminals were 13.12 ± 1.05, 35.29 ± 3.58, 17.66 ± 1.95, 30.18 ± 1.10 and 9.95 ± 1.29, respectively, for glucose, lactate, 3-hydroxybutyrate, glutamine and malate, demonstrating that all substrates were oxidized at a higher rate by synaptic terminals than by astrocytes. The addition of AOAA decreased the rate of ¹⁴CO₂ production from labelled lactate by 57% suggesting that the use of lactate for energy in synaptic terminals is tightly coupled to the activity of the malate-aspartate shuttle. AOAA had no effect on the rate of ¹⁴CO₂ production from labelled glutamine, demonstrating that exogenous glutamine enters the TCA cycle in synaptic terminals via glutamate dehydrogenase, not via transamination as is the case with astrocytes. AOAA had no significant effect on the rates of oxidation of glucose, 3-hydroxybutyrate-and malate by synaptic terminals. These findings demonstrate that inhibiting transamination with AOAA had very different effects on the oxidation of energy substrates in the two preparations, suggesting that the regulation of metabolism is quite different in astrocytes and synaptic terminals. These studies also underscore the importance of utilizing multiple energy substrates since the presence of AOAA altered energy metabolism in some, but not all, co...

SUMMARY Endocannabinoids are widely regarded as negative modulators of presynaptic release. Here we present evidence that in visual cortex endocannabinoids are crucial for the maturation of GABAergic release. We found that between eye opening and puberty, release changes from an immature state with high release probability, short-term depression (STD) and high release variability during irregular patterned activity, to a mature state with reduced release probability, STD and variability. This transition requires visual experience and stimulation of CB1 cannabinoid receptors as it is mimicked by administration of CB1 agonists, blocked by antagonists and is absent in CB1R KO mice. In immature slices, activation of CB1 receptors induces long-term depression of inhibitory responses (iLTD), and a reduction in STD and response variability. Based on these findings, we propose that visually induced endocannabinoid-dependent iLTD mediates the developmental decrease in release probability, STD and response variability, which are characteristic of maturation of cortical GABAergic inhibition.

SUMMARY Neuromodulatory input, acting on G-protein coupled receptors, is essential for the induction of experience-dependent cortical plasticity. Here we report that G-coupled receptors in layer II/III of visual cortex control the polarity of synaptic plasticity through a pull-push regulation of LTP and LTD. In slices, receptors coupled to Gs promote LTP while suppressing LTD; conversely, receptors coupled to Gq11 promote LTD and suppress LTP. In vivo, the selective stimulation of Gs- or Gq11-coupled receptors brings the cortex into LTP-only or LTD-only states, which allows the potentiation or depression of targeted synapses with visual stimulation. The pull-push regulation of LTP/LTD occurs via direct control of the synaptic plasticity machinery and it is independent of changes in NMDAR activation or neuronal excitability. We propose these simple rules governing the pull-push control of LTP/LTD form a general metaplasticity mechanism that may contribute to neuromodulation of plasticity in other cortical circuits.

We would like to correct a mistake in Figure 2 of our paper. During the construction of the figures, we inadvertently plotted an incorrect data set in panel (E) of Figure 2. That panel should show the effects of butaprost on the pre-then-post pairing. Instead, we plotted the post-then-pre data, which are shown in panel (F). We now provide the corrected figure.