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. Author manuscript; available in PMC: 2022 Sep 15.
Published in final edited form as: Biol Psychiatry. 2021 Sep 15;90(6):356–358. doi: 10.1016/j.biopsych.2021.06.014

Figure 1. mGlu3- and mGlu5-mediated hippocampal synaptic plasticity.

Figure 1.

(A) In the absence of mGlu3 activation, mGlu5 interacts with Homer protein to engage the PI3K/Akt/GSK3β pathway, resulting in the internalization of AMPA receptors and generation of LTD. (B) In the PCP model of schizophrenia, NMDA receptor hypofunction has been linked to increased inhibitory tone onto the hippocampal pyramidal cells, resulting in impaired LTP (10). (C) Activation of mGlu3 switches mGlu5-mediated plasticity towards the generation of LTP by promoting endocannabinoid-mediated inhibition of GABAergic interneurons (disinhibition) to drive hippocampal pyramidal cells, resulting in increased NMDA receptor function. mGlu3 and mGlu5, metabotropic glutamate receptor subtypes 3 and 5; PI3K, phosphoinositide 3-kinase; Akt, known as protein kinase B (PKB); GSK3β, glycogen synthase kinase 3β; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; LTD, long-term depression; NMDA, N-methyl-D-aspartate receptor; LTP, long-term potentiation; 2-AG, 2-arachidonoylglycerol; CB1, cannabinoid receptor type 1. Grey indicates hypofunction.