Persistent increase in ventral hippocampal long‐term potentiation by juvenile stress: A role for astrocytic glutamine synthetase

Abstract

A traumatic childhood is among the most important risk factors for developing stress‐related psychopathologies such as posttraumatic stress disorder or depression later in life. However, despite the proven role of astrocytes in regulating transmitter release and synaptic plasticity, the contribution of astrocytic transmitter metabolism to such stress‐induced psychopathologies is currently not understood. In rodents, childhood adversity can be modeled by juvenile stress exposure, resulting in increased anxiety, and impaired coping with stress in adulthood. We describe that such juvenile stress in rats, regardless of additional stress in adulthood, leads to reduced synaptic efficacy in the ventral CA1 (vCA1) Schaffer collaterals, but increased long‐term potentiation (LTP) of synaptic transmission after high‐frequency stimulation. We tested whether the glutamate–glutamine‐cycle guides the lasting changes on plasticity observed after juvenile stress by blocking the astrocytic glutamate‐degrading enzyme, glutamine synthetase (GS). Indeed, the pharmacological inhibition of GS by methionine sulfoximine in slices from naïve rats mimics the effect of juvenile stress on vCA1‐LTP, while supplying glutamine is sufficient to normalize the LTP. Assessing steady‐state mRNA levels in the vCA1 stratum radiatum reveals distinct shifts in the expression of GS, astrocytic glutamate, and glutamine transporters after stress in juvenility, adulthood, or combined juvenile/adult stress. While GS mRNA expression levels are lastingly reduced after juvenile stress, GS protein levels are maintained stable. Together our results suggest a critical role for astrocytes and the glutamate–glutamine cycle in mediating long‐term effects of juvenile stress on plasticity in the vCA1, a region associated with anxiety and emotional memory processing.

Long-Term Impact of Early-Life Stress on Hippocampal Plasticity: Spotlight on Astrocytes

“…Using JS as a model, we showed that the observed reduction in GAT-3 in the dorsal dentate gyrus indeed shifts inhibition in STP protocols after JS, but not stress in adulthood [122]. In parallel, JS appears to affect long-term plasticity in the ventral CA1 by affecting glutamine synthetase and the glutamate/glutamine cycle [120]. Similar studies that combine expression analyses of astrocyte-specific factors with pharmacological interventions are, unfortunately, yet lacking for other early-life stress models such as MS or limited nesting.…”

“…Increased LTP could be normalized in slices of juvenile stressed rats by supplementing glutamine. The expression of glutamine synthetase mRNA was also reduced in the stratum radiatum, the layer of SC synapses in CA1 [120]. Both studies demonstrated that a combined analysis of functional astrocytic domains may help to understand how this cell type shapes lastingly plasticity.…”

“…In contrast to the studies investigating the impact of MS on hippocampal physiology, the differential impact of stress during the postweaning/adolescence period on VH vs. DH plasticity has been investigated more extensively. We and others have consistently shown that stress exposure (PND 27–29 or PND 28–30) during juvenility prompts the induction and maintenance of LTP at the ventral SC-CA1 synapse, while decreasing it somewhat in the dorsal counterpart later in adulthood (PND 60–120) [ 118 , 119 , 120 ]. Strikingly, the combination of JS with acute stress during adulthood further promotes the stabilization of this discrepancy in the ability to express LTP in the VH.…”

Allostatic gene regulation of inhibitory synaptic factors in the rat ventral hippocampus in a juvenile/adult stress model of psychopathology

“…In the current study, we utilized juvenile stress (JS) as a rat model for childhood adversity, a prominent risk factor for developing anxiety disorders and depression as well as cognitive decline later in life (Brunson et al, 2005;Heim & Nemeroff, 2001;McLaughlin et al, 2010). Following JS, we previously reported increased plasticity in the ventral CA1 in association with decreased neurotransmitter metabolism in astrocytes mediated by the enzyme glutamine synthetase (Ivens et al, 2019). Now, we set out to investigate the longterm expression regulation of neuronal factors of GABAergic and glutamatergic transmission in the ventral and dorsal CA1 following JS and its interaction with a subsequent stress experience in adulthood.…”

Potential protective role of astrocytes in the pathogenesis of astrocyte-mediated synaptic plasticity of Parkinson’s disease

“…This type of astrocyte stimulation in the hippocampus increases glutamate release and leads to NMDAindependent LTP production [116]. Furthermore, evidence indicates that astrocytes can modulate LTP by regulating glutamate levels at the synapse and by releasing cofactors of glutamate receptors at the neurons [128].…”