Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia

Abstract

Motor deficits are present in cardiac arrest survivors and injury to cerebellar Purkinje cells (PCs) likely contribute to impairments in motor coordination and post-hypoxic myoclonus. NMDA receptor mediated excitotoxicity is a well-established mechanism of cell death in several brain regions, but the role of NMDA receptors in PC injury remains understudied. Emerging data in cortical and hippocampal neurons indicates that the GluN2A-containing NMDA receptors signal to improve cell survival and GluN2B-containing receptors contribute to neuronal injury. This study compared neuronal injury in the hippocampal CA1 region to that in PCs and investigated the role of NMDA receptors in PC injury in our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Analysis of cell density demonstrated a 24% loss of PCs within 24 hours after 8 min CA/CPR and injury stabilized to 33% by 7 days. The subunit promiscuous NMDA receptor antagonist MK-801 protected both CA1 neurons and PCs from ischemic injury following CA/CPR, demonstrating a role for NMDA receptor activation in injury to both brain regions. In contrast, the GluN2B antagonist, Co 101244, had no effect on Purkinje cell loss while protecting against injury in the CA1 region. These data indicate that ischemic injury to cerebellar PCs progresses via different cell death mechanisms compared to hippocampal CA1 neurons.

Sirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels

“…Some differences in survival and ischemic time were observed in TRPM2 KO mice (Table 1). CA/CPR resulted in delayed neuronal cell death in the CA1 region of the hippocampus, as previously described (Kofler et al, 2004; Allen et al, 2011; Quillinan et al, 2015). We tested the ability of the Sirt2 inhibitor AGK to protect neurons against cerebral ischemia.…”

PSD-93 mediates the crosstalk between neuron and microglia and facilitates acute ischemic stroke injury by binding to CX3CL1

“…In addition, PSD-93 can bind to NR2A and nNOS and facilitate ischemic brain injury [16,31] . On the other hand, neuronal excitatory toxicity interacted with microglia-induced inflammatory response in ischemic brain injury [32][33] . After ischemic stroke, neurons activate microglia through a variety of neurotransmitters or regulators such as glutamate, fractalkine (FKN, CX3CL1), and NO.…”

“…As mentioned above, excitatory amino acid toxicity of neurons interacts with microglial-induced inflammatory responses in cerebral ischemia-reperfusion injury [17,18] . After ischemic stroke, neurons activate microglia through a variety of regulatory factors, and the activation of NMDAR is closely related to the activation of microglia [3] .…”

Endogenous level of TIGAR in brain is associated with vulnerability of neurons to ischemic injury

“…This pattern of TIGAR expression was correlated with the sensitivity of neurons to ischemia/reperfusion insult. [28][29][30][31] . For example, many studies have reported that the expression of NMDA receptor subunits changes during neuronal development [28,32] .…”