Synaptic Long Term Depression

Long term depression (LTD) in the Purkinje cells of the cerebellum is described as a cellular model for information storage and synaptic plasticity. When two inputs to a Purkinje cell (PC), one from a climbing fiber (CF) and the other from a set of granule cell axons (parallel fiber; PF), are repeatedly associated, there is a decrease in the synaptic strength between PF and Purkinje cells PCs. PF is thought to transmit its signal through glutamate and nitric oxide (NO) and CF is thought to transmit its signal through glutamate, corticotropin-releasing factor (CRF) and insulin-like growth factor I (IGF-I).Both PF- and CF-mediated signals are transmitted into PCs through multiple signaling pathways. Glutamate signals in PCs via metabotropic (mGLUR) as well as ionotropic receptors like -amino-3-hydroxy-5-methyl-4-isoxazolone-propionate (AMPA) receptors. The activation of the G protein coupled mGLUR leads to the activation of phospholipase A2 (PLA2) and Phospholipase C (PLC) pathways while AMPA receptor activation triggers the LYN kinase. Glutamate can also activate voltage gated calcium channels (VGCC) via AMPR to increase Ca2+ flux into the cytosol, which in turn triggers Ca2+ release from internal sources. Signaling by NO triggers the RAS/RAF/mitogen-activated protein (MAP) kinase pathway. The activation of the afore mentioned pathways as well signaling by IGF-1 and CRF leads to the phosphorylation of AMPA receptors largely via protein kinase C (PKC). In addition NO released by PF inhibits protein phosphatase through the cGMP/soluble guanylnyl cyclase (sGC) pathway, resulting in inhibition of the dephosphorylation of AMPA receptors. Therefore, the signals from PF and CF regulate the phosphorylation of AMPA receptors through the PKC and protein phosphatase pathways. The phosphorylation of post synaptic AMPA receptors resulting in their clathrin mediated endocytosis is one of the key steps required for cerebellar LTD expression.This pathway highlights the important molecular interactions leading to long term depression in the cerebellum.