Ephrins in astrocytes: synaptic erasers on stage

Among glia cells, astrocytes actively regulate the shaping and functions of the “tripartite synapse” [1]. Changes in synapses may influence diverse biological processes including long-term memory or the shift from acute to chronic pain, which can be dysfunctional in neuropsychiatric disorders such as major depressive disorder (MDD) or in neuropathic pain (NP), respectively [2]. Long-term potentiation (LTP) is considered a major cellular component of memory storage and relies on stabilization of synaptic changes dependent on the activation of several signalling pathways such as the Extracellular signal-Regulated Kinase/Mitogen Activated Protein Kinase (ERK/MAPK) pathway [3]. However, regional and cell-type specific localizations of ERK activity after LTP induction had never been characterized. The ERK pathway is also altered in animal models of depression and decreased levels of its downstream effectors ERK1 and ERK2 characterize post-mortem brains of depressive patients [4], indicating the high biomedical relevance of its pharmacological targeting to reverse aberrant behavioral phenotypes. Combining electrophysiology and immunohistochemistry, we showed that ERK signalling was increased in the stratum radiatum, but not in the stratum pyramidale, of the CA1 region of the hippocampus after LTP induction and a short-term administration of the antidepressant desipramine (DMI) to acute brain slices inhibited ERK activation and attenuated LTP. Additionally, ERK activity was peaking exclusively in astrocytes, but not in neurons of neither stratum, and this activation was prevented by DMI administration [2]. Simultaneously, transcription of the activity-dependent immediate early-gene (IEG) Arc/ Arg 3.1 (Activity-regulated cytoskeleton-associated gene/ Activity regulated gene 3.1) was enhanced in neurons of the stratum pyramidale, but its sustained activation was prevented by DMI treatment. As Arc is usually induced by ERK, but ERK was not affected neither by LTP induction nor by DMI in neurons, we investigated whether drug administration might have indirectly influenced neuronal Arc expression and LTP upon modulation of both the astrocytic ERK and the molecular glia/neuron interface in the stratum radiatum. A study by Filosa and colleagues had previously revealed that the ephrinA3/EphA4 receptor system, which acts as an essential bidirectional glia/ neuron communication mechanism, modulates several physiological processes including proper LTP induction and the shaping of neuronal synapses [5]. The EphA —> ephrinA activation is called “reverse signaling”, whereas the ephrinA —> EphA activation is called “forward signaling” (Figure 1). We postulated that its regulation by DMI treatment in the stratum radiatum of the CA1 might have been relevant in our experiments to induce an astrocyte-dependent synaptic remodeling during neuronal activity. Our findings indeed revealed that the administration of DMI to acute brain slices triggered