FIGURE 11.

Schematic representation of GLAST regulation in relation to nNOS/NO signaling. The left side of the figure depicts a glutamatergic PN synapse in the absence of nNOS‐derived NO signaling, while the right side depicts a physiological glutamatergic synapse with nNOS expression and NO production. (1.a) PF stimulation triggers the production of NO via calcium‐dependent nNOS. (1.b) NO production can also be stimulated by glutamate uptake within BG, again through a calcium‐dependent mechanism. (2) Glutamate released by PFs/CFs are uptake by GLAST and co‐transported with 3 Na⁺ ions into the BG cytosol. Right side: (3.a) NO produced by both PF terminals and BG will activate PKG through the classical NO‐cGMP‐PKG pathway, causing transport of GLAST to the BG PM. (4.a) Additionally, the increased Na⁺ influx through GLAST activity, along with the presence of NO, causes a reversal of the NCX, allowing for Na⁺ to be shuttled outside of the BG and causing an influx of Ca²⁺ into the BG. (5.a) As a result, appropriate glutamate clearance from the synaptic cleft occurs, contributing to the normal function of PNs in the cerebellum. Left side: (3.b) In the absence of nNOS/NO signaling, there is less activation of PKG and therefore less transport of GLAST to the BG PM. (4.b) Additionally, the lack of NO and lower Na⁺ from active GLAST transporters results in lower activity of the NCX in reverse mode and less Ca²⁺ influx into the BG cytosol, which can cause BG process retraction and less BG ensheathment of the synaptic cleft. (5.b) As a result, the decrease in glutamate uptake efficiency will result in an overload of glutamate in the synaptic cleft, leading to PN excitotoxicity