FIGURE 3.

Summary of some future therapeutic targets aimed at restoring normal synaptic physiology. (A) Mechanisms targeting individual synapses. This includes targeting short- and long- term plasticity (STP and LTP, respectively) at the synapse, modulation of muscarinic receptor and NMDA receptor activity, and targeting aberrant activity of non-neuronal cells such as microglia and astrocytes on synapses. (B) Therapeutic mechanisms at the local synaptic level. This includes reducing hyperexcitability or restoring E/I imbalance, preventing excitotoxicity, increasing GABAergic tone, and evaluating the effect of aberrant homeostatic synaptic plasticity. The example images show an imbalance of excitation and inhibition with more excitation as has been described in the literature. Next shows one mechanism of homeostatic synaptic plasticity, synaptic scaling, with either abnormal increases or decreases in synaptic strength by altering the number of receptors present at the post-synaptic density. (C) Therapeutic mechanisms that could be utilized to rescue network activity including optogenetic modulation of the activity of subpopulations of neurons (as shown in the pictogram), stimulation of neurons at gamma-band frequency, and more sophisticated closed-loop network modulation to attempt to recover activity to normal physiological set points following deviations.