Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression

Abstract

Depression is usually associated with alterations in the monoaminergic system. However, new evidences suggest the involvement of the glutamatergic system in the aetiology of depression. Here we explored the glutamatergic system in a rat model of depression (i.e., the flinders sensitive line (FSL)) to reveal the mechanism underlying the emotional and cognitive aspects associated with the disease. We showed a dramatically elevated level of baseline glutamatergic synaptic transmission by whole-cell recordings as well as impairment in long-term potentiation induced by high-frequency stimulation in hippocampal slices from FSL rats compared with Sprague-Dawley rats. At behavioural level, FSL rats displayed recognition memory impairment in the novel object recognition test. Enantioselective chromatography analysis revealed lower levels of D-serine in the hippocampus of FSL rats and both synaptic plasticity and memory impairments were restored by administration of D-serine. We also observed dysfunctional astrocytic glutamate regulation including downregulation of the glia glutamate transporter GLAST as shown by western blot. One possibility is that the dysfunctional astrocytic glutamate reuptake triggers a succession of events, including the reduction of D-serine production as a safety mechanism to avoid NMDA receptor overactivation, which in turn causes the synaptic plasticity and memory impairments observed. These findings open up new brain targets for the development of more potent and efficient antidepressant drugs.

Synaptic Mechanisms Underlying Rapid Antidepressant Action of Ketamine

“…First, increased baseline glutamatergic transmission may be a player in the pathophysiology of depression. This proposal is supported by a recent study that uncovered enhanced basal glutamatergic transmission in a rat model of depression (40). Moreover, several studies support the involvement of increased glutamate release in the context of depression and stress-related behaviors (41).…”

FGF2 alleviates PTSD symptoms in rats by restoring GLAST function in astrocytes via the JAK/STAT pathway

“…The distribution and the expression levels of GLAST and GLT-1 have been studied widely in brain injury and other neurological disorders (Mitosek-Szewczyk et al, 2008;Rao et al, 1998). Additionally, emerging studies have explored the glutamatergic system in a depression model and revealed the mechanism underlying the emotional and cognitive factors associated with depression (Gomez-Galan et al, 2013;Zhu et al, 2014). Evidence has emphasized that the dysfunction of astrocytic glutamate regulation, including the down-regulation of the glial glutamate transporter GLAST, is involved in both synaptic plasticity and memory impairments (Gomez-Galan et al, 2013;Potier et al, 2010).…”

“…Additionally, emerging studies have explored the glutamatergic system in a depression model and revealed the mechanism underlying the emotional and cognitive factors associated with depression (Gomez-Galan et al, 2013;Zhu et al, 2014). Evidence has emphasized that the dysfunction of astrocytic glutamate regulation, including the down-regulation of the glial glutamate transporter GLAST, is involved in both synaptic plasticity and memory impairments (Gomez-Galan et al, 2013;Potier et al, 2010). In Parkinson's disease, studies have demonstrated an association between disrupted glutamatergic neurotransmission and glutamate transporter functioning; however, to our knowledge, the relationship between glutamate transporters and PTSD is unknown.…”

Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders

“…Instead, a reduction in astroctyte number most consistently correlated with regions with reduces volumes [77]. Later in stress-based rodent models, pervasive astrocytic deficits were widely reported including cell loss [78–81] and decreased glutamate uptake from the synaptic cleft [82–84]. Apart from their extensively characterized roles in demyelinating disorders, such as multiple sclerosis and leukodystrophies, OL-lineage cells have been heavily implicated in schizophrenia.…”