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Updated: Apr 25, 2026
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
Co-activation of synaptic and extrasynaptic NMDA receptors by neuronal insults determines cell death in acute brain
Zhuoyou Chen1, Quan Zhou2, Min Zhang1
1Department of Neurology, Laboratory of Neurological Diseases, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, 29 Xinglong Alley, Changzhou, Jiangsu 213003, China.
Abstract:
Overactivation of NMDA receptors is linked to cell death during neuronal insults. However the precise role of synaptic and extrasynaptic NMDA receptors remains to be further determined. In this study, we used the acute brain slice to examine the contributions of synaptic and extrasynaptic NMDA receptors to neuronal death. By activation of synaptic NMDA receptors with bath application of 100 μM bicuculline in acute brain slices, we observed a significant up-regulation in activation of neuronal survival-related signaling (p-CREB, p-ERK1/2 and p-AKT), without an obvious increase of LDH release and neuronal death. Interestingly, activation of extrasynaptic NMDA receptors alone by high dose of glutamate (200 μM) following blockade of synaptic NMDA receptors with co-application of 20 μM MK801 and 100 μM bicuculline, we failed to observe inhibition of neuronal survival signaling and neuronal damage. In contrast, co-activation of synaptic and extrasynaptic NMDA receptors by applying 200 μM glutamate or oxygen-glucose deprivation (OGD) to acute brain slices for 30 min, we observed a significant inhibition of CREB, ERK1/2 and AKT activation, an increase of LDH release and neuronal condensation. Together, co-activation of synaptic and extrasynaptic NMDA receptors by neuronal insults contributes to cell death in acute brain slice.
Insights
Overactivation of both synaptic and extrasynaptic NMDA receptors contributes to neuronal death during brain insults. Activating only synaptic NMDA receptors promotes neuronal survival signaling, while extrasynaptic activation alone does not cause damage.
Area of Science:
- Neuroscience
- Cell Biology
- Neuroprotection
Background:
- Overactivation of N-methyl-D-aspartate (NMDA) receptors is implicated in neuronal death following brain injury.
- The distinct roles of synaptic and extrasynaptic NMDA receptors in this process require further elucidation.
Purpose of the Study:
- To investigate the differential contributions of synaptic and extrasynaptic NMDA receptors to neuronal death in acute brain slices.
- To determine the signaling pathways modulated by NMDA receptor activation during insults.
Main Methods:
- Utilized acute brain slices to study NMDA receptor function.
- Employing bicuculline to activate synaptic NMDA receptors.
- Using glutamate and MK801 to selectively activate or block synaptic and extrasynaptic NMDA receptors.
- Assessed neuronal survival signaling (p-CREB, p-ERK1/2, p-AKT) and neuronal death markers (LDH release, condensation).
- Induced insults using oxygen-glucose deprivation (OGD).
Main Results:
- Activation of synaptic NMDA receptors alone upregulated survival signaling (p-CREB, p-ERK1/2, p-AKT) without inducing cell death.
- Selective activation of extrasynaptic NMDA receptors did not inhibit survival signaling or cause damage.
- Co-activation of both synaptic and extrasynaptic NMDA receptors, or OGD, inhibited survival signaling and led to neuronal death (increased LDH release, condensation).
Conclusions:
- Co-activation of synaptic and extrasynaptic NMDA receptors is crucial for mediating neuronal death during acute brain insults.
- Targeting specific NMDA receptor populations may offer therapeutic strategies for neuroprotection.
