The Yin and Yang in depression: How astrocytes and neurons differentially respond to antidepressants to remodel neuronal synaptic contacts.

BARBARA DI BENEDETTO; SEBASTIAN A. GIUSTI; ANNETTE M. VOGL; THEO REIN; DAMIAN REFOJO; REINER RUPPRECHT

Berlin

Congreso; XI European Meeting on Glial Cells in Health and Disease; 2013

Network Glia , Max Delbrück Centrum für Molekulare Medizin (MDC) Berlin-Buch

Functional alterations in synaptic contacts have often been described as a hallmark of major depressive disorder (MDD). Antidepressants (ADs) have been shown to restore neuronal circuits through an enhancement of synaptogenesis in some regions of the brain. Nevertheless, the underlying mechanisms are still unclear. Glia cells have been since long acknowledged as active partners of neurons in orchestrating molecular signals crucial for the proper arrangement of neuronal circuits in the developing and adult brain. Therefore, understanding how both neurons and astrocytes respond to antidepressants (AD) is of high interest. Using rat C6 glioma cells and primary cultures of astrocytes and neurons, we showed a time-dependent cell autonomous modulation of the ERK/MAPK signalling pathway after acute treatment with various classes of ADs in both cell types. Specifically, glia cells responded to ADs with the simultaneous and fast activation (after 10 min treatment) of both ERK1/2, in contrast to treatment with antipsychotics or mood stabilizers. This activation induced 48 hrs later an increased release of GDNF, a factor involved in synapse formation and axonal wiring, which was MAPK-dependent. On the contrary, hippocampal neurons showed a reduction in ERK activity that correlated with neuronal activity inhibition after short term (10 min) ADs administration, as demonstrated by quantification of c-Fos expression after KCl stimulation. Interestingly, this inhibitory effect was reversible after long term (48 hrs) Ads treatment. To further identify whether GDNF released from astrocytes treated with ADs might be responsible for long term changes in neuronal synapses, we examined how ADs influenced synaptic densities in neurons alone or co-cultured with astrocytes. Strikingly, we found that the number of synapses was reduced at 48hrs after AD treatments, but only in the presence of intact astrocytes and not in cultures of neurons alone or neurons treated with astrocyte-conditioned media. This effect was reversed after 120 hrs treatment and rescued by the soluble form of the specific GDNF receptor GFRalpha1, but not by GDNF alone. Moreover, live imaging of astrocytes showed dramatic morphologic changes of their processes in response to ADs that might underlie the observed synaptic remodelling. Our analysis of changes occurring at the neuronglia interface upon AD treatments might elucidate novel mechanisms of ADs action that may open the avenue for unravelling the role of astrocytes in psychiatric diseases and implement pharmacologic treatment regimens for MDD patients.