Synaptic structure and function in WT, SAPAP3 KO, and psilocybin-treated SAPAP3 KO mice. (IMAGE)
Caption
Synaptic structure and function in WT, SAPAP3 KO, and psilocybin-treated SAPAP3 KO mice. (A) Wild-type (WT) mice: At the presynaptic terminal, action potentials open voltage gated calcium channels (VGCCs), allowing Ca2+ influx. Calcium binds to synaptotagmin, triggering vesicle fusion and the release of brain-derived neurotrophic factor (BDNF) and glutamate into the synaptic cleft. Glutamate activates postsynaptic AMPA and NMDA receptors (AMPAR and NMDAR). AMPAR-mediated Na+ influx depolarizes the dendritic spine, relieving the Mg2+ block on NMDAR’s and allowing Ca2+ entry. These receptors are anchored by the postsynaptic scaffold composed of PSD-95, SAPAP3, Shank, and Homer proteins which play a crucial role in synaptic plasticity. BDNF bind to TrkB receptors, activating CaMKII and supporting synaptic plasticity. mGluR5 modulates additional metabotropic signaling. (B) SAPAP3 knockout (KO) mice (untreated): There is no direct evidence that BDNF release is reduced in SAPAP3 KO mice, but changes to the postsynaptic structure may affect how BDNF signals through its receptor, TrkB. Without SAPAP3, the scaffold that holds key receptors like AMPARs and NMDARs together becomes unstable due to the poor receptor anchoring. This increases mGluR5 activity and weakens AMPAR signaling. As a result, this could lead to impaired synaptic plasticity and behavior. (C) Psilocybin treated SAPAP3 KO mice: Psilocybin normalizes presynaptic Ca2+ influx and restores glutamate release via synaptotagmin-dependent exocytosis. In the synaptic cleft, psilocin may bind directly to TrkB dimers, stabilizing them in a conformation that enhances responsiveness to endogenous BDNF, however, evidence is mixed. Psilocin also accesses both surface and intracellular 5-HT2A receptor pools. 5-HT2A receptors mediate hallucinogenic responses and contribute to structural plasticity. Despite this, psilocybin-induced plasticity may occurs independently of the 5-HT2A receptor via direct TrkB activation. Postsynaptically, TrkB signaling re-engages CaMKII and promotes AMPAR trafficking, potentially rescuing aspects of the disrupted postsynaptic scaffold and potentially mediating long-term therapeutic behavioral outcomes
Credit
Thibault Renoir
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CC BY