MITOCHONDRIAL FISSION AS A KEY REGULATOR OF BDNF-MEDIATED SYNAPTIC REMODELING

Brain-Derived Neurotrophic Factor (BDNF) plays a crucial role in the regulation of synaptic activity and as mediator of long-term potentiation (LTP) at hippocampal synapses. Additionally, synaptic activity influences mitochondrial fission, and its dynamic regulation is essential for inducing synaptic plasticity in the hippocampus. Considering the role of mitochondrial fission in LTP formation and BDNF's pivotal role in LTP induction, we proposed that BDNF's impact on synaptic potentiation might be mediated through mitochondrial fission. We observed that BDNF stimulation of cultured hippocampal neurons enhances the local dendritic synthesis of DRP1, a critical mediator of mitochondrial fission. FUNCAT-PLA experiments demonstrated that BDNF increases the 'de novo' production of DRP1 within the dendritic compartment and at synapses of hippocampal neurons. Moreover, immunocytochemistry experiments indicated that BDNF stimulation upregulates DRP1 phosphorylation at Serine 616, which is known to accelerate mitochondrial fission, in dendrites of hippocampal neurons. We also examined BDNF's effects on mitochondrial dynamics in the dendritic compartment by labeling mitochondria through mito-DsRed transfection. We observed an overall increase in mitochondrial dynamics following BDNF stimulation of hippocampal neurons. Furthermore, inhibiting DRP1 with P110 reduced LTP in hippocampal CA1 synapses (upon theta burst-stimulation), and this effect was not cumulative with the inhibition by TrkB-Fc, which blocks the action of endogenous BDNF. Moreover, inhibition of DRP1 with P110 prevents the increase in surface synaptic expression of NMDA receptors upon BDNF stimulation in hippocampal neurons. These findings underscore the crucial role of mitochondrial dynamics in BDNF's mediation of synaptic plasticity in the hippocampus.
(Supported by FCT [PTDC/MED-NEU/3736/2020])