Figure 4.

Dysregulation of GSK-3 as a potential causal factor in neurodegeneration. NMDAR-LTD results in a reduction in the number of AMPARs at synapses. It can lead to the removal of all AMPARs (termed “silencing”) and synapse elimination, via the process of synaptosis (localized apoptosis). This process is likely to be prominent early in development, where it may be important for the pruning of unwanted synaptic connections. During adulthood it may be more tightly regulated so that LTD involves mainly reductions in synaptic efficacy rather than the elimination of synapses. In particular, synapses that experience regular LTP will have the activity of GSK-3 dampened, by virtue of the PI3K-Akt pathway. In response to stressors (genetic, epigenetic, or environmental) the same mechanisms may be rekindled, resulting in unwanted synaptic elimination. In this example, the dysregulation of GSK-3β activity is due to activation of caspases leading to cleavage of Akt.