TrkB‐mediated activation of the phosphatidylinositol‐3‐kinase/Akt cascade reduces the damage inflicted by oxygen–glucose deprivation in area CA 3 of the rat hippocampus

The selective vulnerability of hippocampal area CA 1 to ischemia‐induced injury is a well‐known phenomenon. However, the cellular mechanisms that confer resistance to area CA 3 against ischemic damage remain elusive. Here, we show that oxygen–glucose deprivation–reperfusion ( OGD ‐ RP ), an in vitro model that mimic the pathological conditions of the ischemic stroke, increases the phosphorylation level of tropomyosin receptor kinase B (TrkB) in area CA 3. Slices preincubated with brain‐derived neurotrophic factor ( BDNF ) or 7,8‐dihydroxyflavone (7,8‐ DHF ) exhibited reduced depression of the electrical activity triggered by OGD ‐ RP . Consistently, blockade of TrkB suppressed the resistance of area CA 3 to OGD ‐ RP . The protective effect of TrkB activation was limited to area CA 3, as OGD ‐ RP caused permanent suppression of CA 1 responses. At the cellular level, TrkB activation leads to phosphorylation of the accessory proteins SHC and Gab as well as the serine/threonine kinase Akt, members of the phosphoinositide 3‐kinase/Akt ( PI ‐3‐K/Akt) pathway, a cascade involved in cell survival. Hence, acute slices pretreated with the Akt antagonist MK 2206 in combination with BDNF lost the capability to resist the damage inflicted with OGD ‐ RP . Consistently, with these results, CA 3 pyramidal cells exhibited reduced propidium iodide uptake and caspase‐3 activity in slices pretreated with BDNF and exposed to OGD ‐ RP . We propose that PI ‐3‐K/Akt downstream activation mediated by TrkB represents an endogenous mechanism responsible for the resistance of area CA 3 to ischemic damage.