Research ReportDexmedetomidine prevents post-ischemic LTP via presynaptic and postsynaptic mechanisms

- DEX, a selective a2-R agonist, could functionally prevent post-ischemic LTP.
- The presynaptic role of it is involved in decreasing glutamate and NE release.
- DEX exerts postsynaptic mechanisms by β-R and PKA regulation.

Increasing evidence indicates that dexmedetomidine (DEX), a selective α2-adrenergic receptor agonist, has a neuroprotective effect against cerebral injury. However, it remains unknown whether and how DEX functionally prevents the pathological form of synaptic plasticity caused by ischemia in the hippocampal CA1 neurons. To address this issue, we analyzed the role of DEX using a model of brain ischemia (oxygen and glucose deprivation, OGD) referred to as post-ischemic LTP (i-LTP). We found that DEX could reduce i-LTP by selectively activating α2 receptors. To clarify its detailed mechanisms, the presynaptic and postsynaptic roles of DEX were investigated. The activation of the α2 receptors of DEX decreased the frequency spontaneous mEPSCs, which exerted its presynaptic mechanisms. In addition, DEX also decreased the amplitude of mEPSCs and prevented the depolarization of postsynaptic membranes during OGD treatment, which exerted its postsynaptic mechanisms. More importantly, our results indicate that postsynaptic β receptors, not α1 receptors, participated in i-LTP. Therefore, these results demonstrated that decreasing β receptors activation by DEX-medicated pre- and post-synaptic α2 receptors activation is responsible for i-LTP. Because of the NMDARs required for i-LTP, we further examined the critical roles of postsynaptic β receptors downstream PKA regulation of NMDA receptor-mediated EPSCs (NMDA EPSC). We clarified that it is attributable to the direct effect of DEX on NMDA EPSC as mediated by PKA inactivation. These findings suggest that DEX can protect neurons from functional damage caused by a relatively mild degree of transient cerebral ischemia, and this effect is mediated by both presynaptic reduction of NE and glutamate release and postsynaptic suppression of NMDAR activation by β receptors and downstream PKA regulation.

A schematic illustration of the presynaptic and postsynaptic mechanisms of DEX in OGD-induced ischemic LTP. The scheme shows that OGD triggers modifications in the pre-and post-synaptic neurons. A brief in vitro ischemic episode causes norepinephrine (NE) and glutamate release from presynaptic sites and induces a membrane depolarization of postsynaptic neurons, thereby activation of β receptor and NMDARs, which triggers ischemic LTP (i-LTP). DEX acting on the pre-synaptic α2 receptor and NE and glutamate release are shown in the presynaptic site. DEX preventing β receptor and NMDARs activation by hyperpolarization of post-neuronal membrane is shown in the postsynaptic site. Therefore, the β receptor-cAMP/PKA intracellular pathway in the postsynaptic sites might involve in the effects of DEX on i-LTP. The red circle represents a blockade of the release of the two neurotransmitters, together with hyperpolarization of postsynaptic neurons, thereby affecting the β receptors downstream PKA, calcium and AMPAR and NMDAR-mediated responses.162