Depression is a great threat to human lifeand health, in which more than 350 million people worldwide are suffering fromdepression. Depression has caused a high rate of disability and suicide, bringinghuge economic burdens and spiritual loss in society and families. In recentyears, studies have found that ketamine under sub-anesthetic doses, acting as achannel 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-sensitiveionotropic glutamate receptors and have a high calcium permeability, which playsan important role in excitatory synaptic transmission. NMDA receptors have twosubtypes, which are GluN2A and GluN2B. More and more studies have shown thatthe NMDA GluN2B receptor plays a very important role in depression. GluN2B selectiveinhibitors can significantly reduce depression-like behaviors, but themechanism of action is still unclear.
On August 24, 2021, the team of Wei Yangand Jianhong Luo from the School of Neuroscience and Brain Medicine at ZhejiangUniversity recently published a research paper “Disrupting phosphorylation ofTyr-1070 at GluN2B selectively produces resilience to depression-like behaviors”in Cell Reports. The article reveals a new mechanism for selectivemodulation of the phosphorylation of the GlN2B subunit tyrosine 1070 of themedial prefrontal cortex (mPFC) NMDA receptor to mediate antidepressant-likebehaviors, which provides a new idea for the treatment of depression.
Researchers have found that thephosphorylation of tyrosine 1070 of the GluN2B subunit can coordinatelyregulate the phosphorylation of tyrosine 1472 to prevent cell membraneinternalization (J Biol Chem, 2015), but the physiological and pathologicalfunctions of this regulatory mechanism remain unclear. Thus, the researchersapplied CRISPR-Cas9 technology to construct genetic mutant mice at Y1070F ofGluN2B. Surprisingly, they found that the mutant mice significantly exhibitedantidepressant-like behaviors with or without 14 days of exposure to chronicrestraint stress (CRS), indicating that mutation at Y1070F of GluN2B selectivelyaffected depression-related behaviors in mice. Further studies revealed thatthe mutant mice decreased the phosphorylation level of GluN2B tyrosine 1472 in themPFC only. The electrophysiological results proved that the function of the synapticNMDA receptor from the 5th pyramidal neurons in mPFC was normal, but the non-synapticGluN2B subtype NMDA receptor function was significantly downregulated,indicating that the tyrosine 1070 site is selectively regulated cell membranelocalization of non-synaptic NMDA receptors in mPFC. On the contrary, thesynaptic NMDA receptors and non-synaptic NMDA receptors from hippocampalpyramidal neurons were unchanged, further clarifying that the mechanism isselective in the brain. Subsequently, the team revealed that the mTORC1activity in the prefrontal cortex of the mutant mice was significantly increasedin the number of neuronal excitatory synapses and thus leading to antidepressant-likebehaviors.
