Neurotrophins play an important role in modulating activity-dependent neuronal plasticity. In particular, threshold levels of brain-derived neurotrophic factor (BDNF) are required to induce long-term potentiation (LTP) in acute hippocampal slices. Conversely, the administration of exogenous BDNF prevents the induction of long-term depression (LTD) in the visual cortex. A long-standing missing link in the analysis of this modulatory role of BDNF was the determination of the time-course of endogenous BDNF secretion in the same organotypic preparation in which LTP and LTD are elicited. Here, we fulfilled this requirement in slices of perirhinal cortex. Classical theta-burst stimulation patterns evoking LTP lasting >180 min elicited a large increase in BDNF secretion that persisted 5-12 min beyond the stimulation period. Weaker theta-burst stimulation patterns leading only to the initial phase of LTP (≈35 min) were accompanied by a smaller increase in BDNF secretion lasting <1 min. Sequestration of BDNF by TrkB-IgG receptor bodies prevented LTP. Low-frequency stimulations leading to LTD were accompanied by reductions in BDNF secretion that never lasted beyond the duration of the stimulation.

Regulation of brain‐derived neurotrophic factor (BDNF) secretion plays a critical role in long‐term potentiation (LTP). It is generally thought that the supply for this secretion is newly synthesized BDNF targeted to the synapse. Here we provide evidence that hippocampal neurons additionally recycle BDNF for activity‐dependent secretion. Exogenously applied BDNF is internalized by cultured neurons and rapidly becomes available for activity‐dependent secretion, which is controlled by the same mechanisms that regulate the secretion of newly synthesized BDNF. Moreover, BDNF recycling replaced the new synthesis pathway in mediating the maintenance of LTP in hippocampal slices: the late phase LTP, which is abolished by protein synthesis inhibition, was rescued in slices preincubated with BDNF. Thus, endocytosed BDNF is fed back to the activity‐dependent releasable pool required for LTP maintenance.

The effect of the assisted zona hatching (AZH) procedure was investigated on 135 cycles with a poor prognosis of pregnancy due to: (i) maternal age > or = 38 years (45 cycles); (ii) three or more failed in-vitro fertilization (IVF) attempts (70 cycles), and (iii) patients possessing both inclusion criteria (20 cycles). The control groups (113 cycles) included patients possessing the same characteristics (42, 53 and 18 cycles respectively) and who did not undergo the AZH procedure. A total of 505 embryos was treated with AZH before transfer, resulting in: 14, 25 and 6 clinical pregnancies. The percentage of clinical pregnancies per cycle was significantly higher than controls for the first (31 vs 10% in control 1, P < 0.05) and second groups (36 vs 17% in control 2, P < 0.05). No significant difference in percentage of clinical pregnancies was found for the third group (30 vs 6%). Similarly, higher rates of implantation were obtained (11.5, 15 and 11%) compared to the respective controls (4%, P < 0.02; 6.3%, P < 0.01; and 1.5%). The rate of miscarriage in the AZH groups was similar to that obtained in the controls (22 vs 21%). Finally, the morphological analysis of the embryos transferred revealed that the poor prognosis condition is associated to a significantly slower rate of development and a higher rate of fragmentation. The present results indicate that AZH procedure improves pregnancy and implantation rates in patients with a poor prognosis of pregnancy by facilitating the hatching process in embryos which would otherwise be trapped inside the zona pellucida.