In the core of a brain infarct, energy supply is insufficient to remain ion gradients across the neuronal plasma membrane: loss of neuronal function is followed by neuronal death within minutes. Surrounding the infarct core there is an area with higher remaining perfusion levels. In this so-called penumbra, neurons are silent, but structurally intact. These may eventually recover, or proceed to cell death, but the mechanisms behind these diverging scenarios are not clearly understood. Therapies to prevent collateral damage of penumbral brain tissue have a large potential to improve neurological outcome of stroke patients, but are lacking. Synaptic failure due to impeded Synapsin-I phosphorylation is responsible for the initial, potentially reversible dysfunction. A pilot study in cultured cortical networks confirmed synaptic failure, and showed largely reduced activity levels, while individual neuronal functioning remained intact. We will investigate the reversibility of the initial synaptic failure, and two putative mechanisms leading to irreversible damage in the absence of primary cell death. First, we hypothesize that, depending on hypoxic depth and duration, apart from energy depletion, synaptic dysfunction may directly lead to secondary neuronal cell death. Here, secondary damage is related to insufficient activation, and we will investigate whether mild activation may delay or reduce cell death. Second, experimental data show that low neuronal activity levels trigger homeostatic processes that up-regulate excitatory connectivity, which may indirectly lead to secondary damage. Namely, the consequent energy demand from homeostatic processes further reduces the amount of ATP available for Synapsin-I phosphorylation and neurotransmitter release, thus creating a vicious circle. Mild activation should also avoid low activity induced homeostatic processes. Additionally, targeted pharmacological treatment will be validated to avoid activity dependent cell death as well as homeostatic interference.