Depression is a great threat to human life and health, in which more than 350 million people worldwide are suffering from depression. Depression has caused a high rate of disability and suicide, bringing huge economic burdens and spiritual loss in society and families. In recent years, studies have found that ketamine under sub-anesthetic doses, acting as a channel blocker for the ionotropic glutamate receptor N-methyl-D-aspartate (NMDA) receptor, can have a rapid and long-lasting antidepressant effect.
NMDA receptors are voltage-sensitive ionotropic glutamate receptors and have a high calcium permeability, which plays an important role in excitatory synaptic transmission. NMDA receptors have two subtypes, which are GluN2A and GluN2B. More and more studies have shown that the NMDA GluN2B receptor plays a very important role in depression. GluN2B selective inhibitors can significantly reduce depression-like behaviors, but the mechanism of action is still unclear.
On August 24, 2021, the team of Wei Yang and Jianhong Luo from the School of Neuroscience and Brain Medicine at Zhejiang University recently published a research paper “Disrupting phosphorylation of Tyr-1070 at GluN2B selectively produces resilience to depression-like behaviors” in Cell Reports. The article reveals a new mechanism for selective modulation of the phosphorylation of the GlN2B subunit tyrosine 1070 of the medial prefrontal cortex (mPFC) NMDA receptor to mediate antidepressant-like behaviors, which provides a new idea for the treatment of depression.
Researchers have found that the phosphorylation of tyrosine 1070 of the GluN2B subunit can coordinately regulate the phosphorylation of tyrosine 1472 to prevent cell membrane internalization (J Biol Chem, 2015), but the physiological and pathological functions of this regulatory mechanism remain unclear. Thus, the researchers applied CRISPR-Cas9 technology to construct genetic mutant mice at Y1070F of GluN2B. Surprisingly, they found that the mutant mice significantly exhibited antidepressant-like behaviors with or without 14 days of exposure to chronic restraint stress (CRS), indicating that mutation at Y1070F of GluN2B selectively affected depression-related behaviors in mice. Further studies revealed that the mutant mice decreased the phosphorylation level of GluN2B tyrosine 1472 in the mPFC only. The electrophysiological results proved that the function of the synaptic NMDA receptor from the 5th pyramidal neurons in mPFC was normal, but the non-synaptic GluN2B subtype NMDA receptor function was significantly downregulated, indicating that the tyrosine 1070 site is selectively regulated cell membrane localization of non-synaptic NMDA receptors in mPFC. On the contrary, the synaptic NMDA receptors and non-synaptic NMDA receptors from hippocampal pyramidal neurons were unchanged, further clarifying that the mechanism is selective in the brain. Subsequently, the team revealed that the mTORC1 activity in the prefrontal cortex of the mutant mice was significantly increased in the number of neuronal excitatory synapses and thus leading to antidepressant-like behaviors.
