Fig. 1. The major signaling pathways involved in regulating spine remodeling and synaptic plasticity, including the NMDA and AMPA glutamate receptor subtypes, neurotrophic factors (i.e., BDNF), and related downstream signaling. (A) Repeated stimulations or strong signals induce the release of neurotransmitters such as glutamate at the presynaptic terminals of the neuron. Glutamate released from presynaptic terminals binds to its receptors (e.g., AMPA, NMDA, mGlu) leading to the release of ions (e.g., calcium, sodium) into the synaptic cleft and AMPAR phosphorylation, which results in the induction of LTP in postsynaptic neurons. Calcium influx through NMDARs and somatic voltage-dependent calcium channels (VDCCs) activate Ca2+/calmodulin-dependent kinase (CaMK) isoforms, cyclic AMP, and phosphatidylinositol pathways, inducing the activation of cyclic AMP-responsive element-binding protein (CREB); this promotes BDNF expression. In dendrites, BDNF is packaged into secretory granules for the regulated secretion pathway and released into the synapse. When secreted BDNF binds its receptor, TrkB, phosphorylated TrkB activates the downstream protein, Akt, followed by the activation of mTOR by p-Akt. Then, mTOR activates two downstream signaling proteins, p70s6k and 4E-BP, and controls local translational activation and local proteins synthesis (GluA1, PSD95) enhancement. (B) Conversely, LTD can be induced by repeated low-frequency stimulation. Weak activity of presynaptic neurons leads to modest depolarization and calcium influx through the NMDA receptors. This preferentially activates phosphatases (protein phosphatase1, PP1), which dephosphorylate AMPA receptors, thus promoting receptor endocytosis and decreased efficacy of the synapse. Chronic stress decreases BDNF and mTORC1 signaling, in part via upregulation of the negative regulator ‘regulated in DNA damage and repair’ (REDD1), which decreases the synthesis of synaptic proteins and thereby contributes to a reduced number of spine synapses.
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