Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype

Abstract

The role of glutamate N-methyl-D-aspartate receptor (NMDAR) hypofunction has been extensively studied in schizophrenia; however, less is known about its role in anxiety disorders. Recently, it was demonstrated that astrocytic GLT-1 blockade leads to an anxiety-like phenotype. Although astrocytes are capable of modulating NMDAR activity through glutamate uptake transporters, the relationship between astrocytic glutamate uptake and the development of an anxiety phenotype remains poorly explored. Here, we aimed to investigative whether long-term antagonism of NMDAR impacts anxiety-related behaviors and astrocytic glutamate uptake. Memantine, an NMDAR antagonist, was administered daily for 24 days to healthy adult CF-1 mice by oral gavage at doses of 5, 10, or 20 mg/kg. The mice were submitted to a sequential battery of behavioral tests (open field, light–dark box and elevated plus-maze tests). We then evaluated glutamate uptake activity and the immunocontents of glutamate transporters in the frontoparietal cortex and hippocampus. Our results demonstrated that long-term administration of memantine induces anxiety-like behavior in mice in the light–dark box and elevated plus-maze paradigms. Additionally, the administration of memantine decreased glutamate uptake activity in both the frontoparietal cortex and hippocampus without altering the immunocontent of either GLT-1 or GLAST. Remarkably, the memantine-induced reduction in glutamate uptake was correlated with enhancement of an anxiety-like phenotype. In conclusion, long-term NMDAR antagonism with memantine induces anxiety-like behavior that is associated with reduced glutamate uptake activity but that is not dependent on GLT-1 or GLAST protein expression. Our study suggests that NMDAR and glutamate uptake hypofunction may contribute to the development of conditions that fall within the category of anxiety disorders.

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

“…There is evidence, however, for the expression of functional NMDA receptors on astrocytes in upper layers of the cortex (Mehina, Murphy‐Royal, & Gordon, ). As such the effects of prolonged NMDA receptor antagonism on glutamate transporter function used in Zimmer et al () could be mediated by direct effects of memantine on astrocytic NMDA receptors. In agreement with the data from Zimmer et al (), injection of a dihydrokainate into the prefrontal cortex of rats, to block glutamate uptake, was found to be sufficient to drive anhedonia‐like behaviors in multiple studies (Bechtholt‐Gompf et al, ; Cui et al, ; John et al, ; Lee, Gaskins, Anand, & Shekhar, ).…”

“…It has been demonstrated that depressive phenotypes can be driven by inducing astrocyte dysfunction alone. It was found long‐term NMDA receptor antagonism by memantine, which acts as an open channel blocker (Lipton, ), induced a reduction astrocytic glutamate transport that correlated with a depressive phenotype (Zimmer et al, ). The link between NMDA receptor antagonism and glutamate transporter function in this model of stress is unclear.…”

“…In contrast to long‐term NMDA receptor antagonism which appears to be able to drive a depressive phenotype (Zimmer et al, ), acute treatment with the NMDA receptor antagonist ketamine has been shown to reduce symptoms of depression (McGirr et al, ) and depressive‐like phenotypes (McGirr, LeDue, Chan, Xie, & Murphy, ). One study investigated the effects of stress on cortical connectivity in situ using mesoscale cortical imaging of glutamatergic transmission in rodent model of depression.…”

Anxiolytic Actions of Exercise in Absence of New Neurons

“…Another consequence of running is the proliferation and growth of astrocytes in the hippocampus of exercised mice (Li et al, 2005;Brockett et al, 2015), which also have lower hippocampal glutamate levels (Biedermann et al, 2012). Anxiety-like behavior is inversely correlated with astrocytic glutamate uptake in the hippocampus (Zimmer et al, 2015), so changes in astrocytic mechanisms involving glutamate in the hippocampus may also mediate decreases in anxiety-like behavior following exercise. Exercise also promotes dendritic growth in the hippocampus (Stranahan et al, 2007), facilitates LTP (van Praag et al, 1999), and affects a wide range of neurotrophic factors, neuropeptides, and neurotransmitters (Bjørnebekk et al, 2006), all of which could potentially affect hippocampal function and alter anxiety-like behavior.…”

Mechanisms of long-term cognitive dysfunction of sepsis: from blood-borne leukocytes to glial cells

“…Terms such as neuro- or gliavascular unit (NVU, GVU) describe the strong influence of the microenvironment on the brain endothelium [ 120 ]. Neighboring cell types such as astrocytes, pericytes, microglia, or even neurons are known to influence the functionality of BBB in health as well as in disease, which is supported by their physical proximity and consequent small diffusion distances for signaling molecules [ 120 , 121 ]. Astrocytes can also downregulate microglial activation by secretion of anti-inflammatory substances such as transforming growth factor (TGF) and prostaglandin E2 (PGE2) [ 122 , 123 ], resembling a M2 phenotype, and may thereby limiting neuroinflammation.…”