Activation of astrocytes has a profound effect on brain plasticity and is critical for the pathophysiology of several neurological disorders including neuropathic pain. Here, we show that metabotropic glutamate receptor 5 (mGluR5), which reemerges in astrocytes in a restricted time frame, is essential for these functions. Although mGluR5 is absent in healthy adult astrocytes, it transiently reemerges in astrocytes of the somatosensory cortex (S1). During a limited spatiotemporal time frame, astrocytic mGluR5 drives Ca2+ signals; upregulates multiple synaptogenic molecules such as Thrombospondin-1, Glypican-4, and Hevin; causes excess excitatory synaptogenesis; and produces persistent alteration of S1 neuronal activity, leading to mechanical allodynia. All of these events were abolished by the astrocyte-specific deletion of mGluR5. Astrocytes dynamically control synaptic plasticity by turning on and off a single molecule, mGluR5, which defines subsequent persistent brain functions, especially under pathological conditions.

Background: Catatonia can arise from various conditions, not only psychiatric but also non‐psychiatric etiologies. This diversity of underlying causes makes it challenging to identify the underlying etiology, which is crucial for appropriate management. Nitrous oxide (N₂O) is widely used for recreational purposes, and its adverse effects have become a growing concern. Chronic exposure can lead to vitamin B12 deficiency, which manifests both neurological and psychiatric symptoms, including catatonia. Vitamin B12 supplementation is an effective treatment, but the diverse clinical manifestations of N₂O toxicity, coupled with the diverse etiologies of catatonia, can delay diagnosis and intervention.Case Presentation: The patient, a healthy man in his 20s, had been receiving N₂O anesthesia regularly for pain relief while undergoing cosmetic hair removal. After his seventh inhalation, he developed a catatonia and was admitted to a previous hospital. After a comprehensive examination failed to identify the etiology, he was transferred to our hospital for psychiatric assessment. Intravenous benzodiazepine failed to improve his catatonia. Re‐evaluation of the underlying etiologies of benzodiazepine‐refractory catatonia raised the possibility of a vitamin B12 deficiency resulting from chronic N₂O exposure. Vitamin B12 supplementation promptly improved his catatonia, and the patient was discharged without any recurrence of his symptoms.Conclusion: Catatonia developed in the present patient after multiple exposures to N₂O. Active vitamin B12 may be administered if N₂O is suspected of causing psychotic symptoms. Moreover, reassessing the differential diagnosis is worthwhile when managing refractory catatonia.

Glial cells are vital for the modulation of synaptic connections and healthy brain development. They control the excitatory / inhibitory synaptic balance and assemble neural circuity by synaptic formation or elimination. We have recently revealed that astrocytes form excitatory synapses in the adult injured brain through mGluR5 signaling. However, astrocytic mGluR5 is, in health brain, expressed in the limited time-window of the postnatal developmental stage. Thus, we surveyed whether / how astrocytic mGluR5 destines the subsequent synaptic assembly using astrocyte-specific mGluR5 KO mice (cKO). Unexpectedly, the number of excitatory synapses did not alter much in cKO, instead, the number of inhibitory synapses decreased significantly in cKO throughout ages. Interestingly, microglia frequently engulfed inhibitory synaptic elements in cKO. Astrocytic mGluR5 expression was transient event in the critical period, however, behavioral dysfunction was observed even in adult cKO mice. Next, we surveyed the astrocytic molecule which regulates microglial engulfment. We focused on astrocytic IL7, which is decreased in cKO, as a candidate for such molecules. IL7 treatment decreased engulfment-related gene expression in microglia. Hence, we conclude that astrocytes organize inhibitory network in the critical period by modulating microglial phagocytic activity. It should be noted that although mGluR5 is only transiently expressed in astrocytes in the critical period, its function greatly affects the inhibitory neuronal networks throughout life.

Alexander disease (AxD) is an intractable neurodegenerative disease caused by mutations in glial fibrillary acidic protein (GFAP), which is predominantly expressed in astrocytes. Thus, AxD is a primary astrocyte disease. However, it remains unclear how GFAP mutations affect astrocytes and cause AxD pathology. Three features are characteristic of AxD astrocytes in vivo: (1) Rosenthal fibers (RFs), the hallmark of AxD; (2) aberrant Ca²⁺ signals (AxCa); and (3) upregulation of disease-associated genes (AxGen). We established a primary culture system for astrocytes from an AxD transgenic mouse model, and used it to analyze the above features of AxD pathogenesis in astrocytes in vitro. We observed the formation of RFs in AxD primary cultures. The abundance of RFs was greater in AxD-transgene-homozygous compared with -hemizygous astrocytes, indicating a gene dosage effect, and this abundance increased with time in culture, indicating a developmental process effect. However, cultured AxD astrocytes did not exhibit changes in either AxCa or AxGen. We therefore conclude that RFs in astrocytes form via a cell-autonomous mechanism, whereas AxCa and AxGen are likely to occur via a non-cell-autonomous mechanism through interactions with other cells, such as neurons, microglia, and vascular cells. Although primary cultured AxD astrocytes are suitable for elucidating the mechanisms of RFs formation and for intervention studies, it should be noted that they cannot reflect the pathophysiology of non-cell-autonomous events in astrocytes.

Introduction: We have already reported the superior feasibility and safety and 3-year outcomes of adjuvant S-1 plus docetaxel in patients with stage III gastric cancer as a prospective phase II study. We report 5-year follow-up data on patients enrolled onto this study.