BDNF isoforms: a round-trip ticket between neurogenesis and serotonin?

FOLTRAN, RB; HITA, F; LOPEZ STEINMETZ, LC; MAROTEAUX L; DIAZ SL

Viena

Congreso; 29th European College of Neuropsychopharmacology Meeting; 2016

European College of Neuropsychopharmacology

Major Depressive Disorder is among the most prevalent neuropsychiatric dysfunctions worldwide, with high rates of resistance to treatment. All of the antidepressant therapies, including those targeting the serotonergic system, increase neuron proliferation and survival in the hippocampus, after chronic administration. However, whereas intact adult hippocampal neurogenesis is required for antidepressant effects, a causative role for neurogenesis in depression is more difficult to confirm. Remarkably, an analogous picture has been described for a neurotrophin extensively implicated in adult neurogenesis, the brain-derived neurotrophic factor, BDNF: while changes in BDNF levels may not directly be involved in the pathophysiology of depression, this neurotrophin could be critical for antidepressants effects. The complex biology of BDNF is given by several factors, namely, the presence of two isoforms with opposite actions: the pro-apoptotic pro-BDNF which is cleaved by proteases to yield the pro-neurogenic mature BDNF (mBDNF).We have first demonstrated a paradoxal increase of cell survival in the hippocampus of three different mice models with profound reductions of serotonin neurotransmission (European Journal of Neuroscience Best Publication Award 2015). We propose now to dissect the BDNF pathway involved in the pro-neurogenic phenotype of hyposerotonergic mice, as well as the functionality of the supernumeraries newborn neurons in these conditions. Hippocampal expression of BDNF isoforms as well as the expression and activity of tPA and MMP-9, proteases responsible for extracellular proBNF cleavage were studied by western blot and zymography. Expression and activation of the proBDNF and mBDNF receptors TrkB and p75, respectively, were also studied. Data were analyzed by Student?s t test. No changes in the expression of pro-BDNF, mBDNF, tPA or MMP-9 were detected in hyposerotonergic mice. However, a significant increased expression of the mBDNF TrkB receptor was detected, in line with the increased cell survival. As hippocampal immature neurons are proposed to have a role in pattern separation tasks, we had first performed contextual fear-discrimination learning, a type of hippocampal-dependent learning test that captures the animal?s ability to discriminate two similar contexts. No significant difference was observed in the performance of hyposerotonergic and wild type mice. To rule out a fear-related behavior deficit in hyposerotonergic mice, we now use a different pattern separation test in which hippocampal memory is studied through spatial location. Again, hyposerotonergic mice have a performance similar to that of wild type mice in the object location task.The proposed experiments pointed to tackle the BDNF pathway at different levels, to unravel how BDNF signaling can modulate the neurogenic processes in the adult hippocampus in a context of serotonin depletion. Indeed, the observed increased activity in the pro-neurogenic pathway mBDNF-TrkB could be linked to the pro-survival phenotype described in serotonin-depleted mice models. However, it is still intriguing the lack of improvement in pattern separation paradigms, considering that immature neurons have been indicated as participating in these tasks. To better understand neural stem cell biology is essential for antidepressant therapies, and more exciting, it will facilitate to focus the search for new and targeted therapies using neural stem cells for a host of neurodegenerative and psychiatric disorders.