Hyperbaric oxygen therapy enhances hippocampal long-term potentiation via upregulation of BDNF and p-CREB1 in rats: Evidence outside pathological models

Abstract

Hyperbaric oxygen therapy (HBOT) is known to confer neuroprotective benefits in injury models, but its in vivo effects on synaptic plasticity in the healthy brain remain unclear. This study investigates HBOT’s impact on hippocampal long-term potentiation (LTP) and underlying molecular mechanisms in adult male Wistar rats. Animals were randomized into Control (ambient air) and HBOT (100 % O₂ at 2.4 ATA for 1 h daily) groups for seven days. On day 8, field potentials were recorded from the dentate gyrus to generate input–output curves for excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude. Time-course responses were then monitored over a 90-minute period using four 100 Hz high-frequency stimulation trains for LTP induction. Following electrophysiology, hippocampal tissue was assayed for pro-BDNF, BDNF, CREB1, and p-CREB1 via immunofluorescence and qPCR. HBOT-treated rats exhibited significantly greater LTP during the maintenance phase: PS amplitude peaked at 233.4 ± 17.9 % versus 130.9 ± 20.1 % in controls (p = 0.0019), and EPSP slope reached 125.0 ± 6.2 % versus 91.6 ± 9.5 % (p = 0.0104). Immunofluorescence revealed elevated pro-BDNF (p = 0.0058), p-CREB1 (p = 0.0011), and p-CREB1/CREB1 ratio (p = 0.0309) while total CREB1 remained unchanged. qPCR confirmed a 2-fold increase in BDNF mRNA (p = 0.0495) without significant change in CREB transcripts. In conclusion, HBOT enhances hippocampal LTP in healthy rats by up-regulating the BDNF/p-CREB1 axis, revealing a novel neuromodulatory effect beyond injury models. These findings open avenues for its use in non-pathological contexts and warrant further mechanistic and translational studies.