Figure 3.

Hypothetical experiment to evaluate the influence of energy availability on synaptic scaling: The influence of energy availability in synaptic plasticity could be evaluated empirically. Here we propose a simple hypothetical scenario and explain what outcomes we predict under each condition. (A) Cultured neurons are stimulated with bicuculine (Bic) for 48 h (denoted by a black bar), which presumably induces transient changes in ATP concentration [A(t)]. Neurons respond by increasing ATP production [P(t)] and reducing ATP consumption [C(t)] by reducing its firing rate, which leads to the reestablishment of homeostatic ATP concentration within the time window enclosed by dotted lines. (B) During stimulation, cultured neurons can be pharmacologically treated to partially inhibit oxidative phosphorylation (i.e., reducing ATP synthesis) denoted by a black arrow. Following the Energy Homeostasis Principle, we propose this will result in a further reduction of ATP concentration, which will induce an accelerated reduction in ATP consumption through the reduction of synapse firing rates. Thus, we propose that in this scenario the time window required to return to homeostasis is shortened. (C) Almost an identical protocol to (B) is applied to neurons; however, using an ATP mimetic molecule (denoted by the black arrow). We assume that ATP mimetic molecules would delay the reduction of synapsis firing rate by allosterically inhibiting AMPK, resulting in an enlarged period of energy consumption. Thus, we propose a wider time window before reaching A_H. All graphics follow Equations 4 and 5, with the additional assumption that the magnitude of the adjustment of P(t) and C(t) are proportional to the distance of ATP levels A(t) to homeostatic levels A_H. Results from these kinds of experiments could advance the understanding (and potentially manipulate) of the mechanisms responsible for neural adaptations, uncovering the relevant role of metabolic elements, such as metabolic sensors and/or nutrient availability.