The beneficial effects of brain-derived neurotrophic factor (BDNF)—a member of the neurotrophin family—on cognitive function or dementia are well established in both rodents and human beings. In contrast, little is known about the association of proBDNF—a precursor protein with opposing neuronal effects of BDNF—with cognitive function in non-demented older adults. We analyzed brain magnetic resonance imaging findings of 256 community-dwelling older adults (mean age of 68.4 years). Serum BDNF and proBDNF levels were measured by quantitative enzyme-linked immunosorbent assay. Logistic regression analysis revealed that older age, less physical activity, hippocampal atrophy, and lower BDNF levels were independently associated with memory impairment determined by the Rivermead Behavioral Memory Test. Path analysis based on structural equation modeling indicated that age, sport activity, hippocampal atrophy and BDNF but not proBDNF were individually associated with Rivermead Behavioral Memory Test scores. These findings suggest that impaired BDNF function, in addition to physical inactivity and hippocampal atrophy, is associated with age-related memory impairment. Therefore, BDNF may be a potential target for dementia prevention.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by deficits in social interaction, difficulties with language, and repetitive/restricted behaviors. Microglia are resident innate immune cells which release many factors including proinflammatory cytokines, nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) when they are activated in response to immunological stimuli. Recent in vivo imaging has shown that microglia sculpt and refine the synaptic circuitry by removing excess and unwanted synapses and be involved in the development of neural circuits or synaptic plasticity thereby maintaining the brain homeostasis. BDNF, one of the neurotrophins, has various important roles in cell survival, neurite outgrowth, neuronal differentiation, synaptic plasticity and the maintenance of neural circuits in the CNS. Intracellular Ca2+ signaling is important for microglial functions including ramification, de-ramification, migration, phagocytosis, and release of cytokines, NO and BDNF. BDNF induces a sustained intracellular Ca2+ elevation through the upregulation of the surface expression of canonical transient receptor potential 3 (TRPC3) channels in rodent microglia. BDNF might have an anti-inflammatory effect through the inhibition of microglial activation and TRPC3 could play important roles in not only inflammatory processes but also formation of synapse through the modulation of microglial phagocytic activity in the brain. This review article summarizes recent findings on emerging dual, inflammatory and non-inflammatory, roles of microglia in the brain and reinforces the importance of intracellular Ca2+ signaling for microglial functions in both normal neurodevelopment and their potential contributing to neurodevelopmental disorders such as ASDs.

Microglia are resident innate immune cells which release many factors including proinflammatory cytokines, nitric oxide (NO) and neurotrophic factors when they are activated in response to immunological stimuli. Recent reports show that pathophysiology of schizophrenia is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling, which is mainly controlled by the endoplasmic reticulum (ER), is important for microglial functions such as release of NO and cytokines, migration, ramification and deramification. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of schizophrenia, while it remains unclear how typical or atypical antipsychotics affect intracellular Ca2+ mobilization in microglial cells. This mini-review article summarizes recent findings on cellular mechanisms underlying the characteristic differences in the actions of antipsychotics on microglial intracellular Ca2+ signaling and reinforces the importance of the ER of microglial cells as a target of antipsychotics for the treatment of schizophrenia.

The pathophysiology of Alzheimer’s disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-d-aspartate (NMDA) receptors used as an anti-Alzheimer’s drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca²⁺ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human β-Amyloid (1–42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca²⁺ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1β, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-β and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human β-Amyloid (1–42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of β-Amyloid (1–42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca²⁺ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.

Oxytocin is deeply involved in human relations. In recent years, it is becoming clear that oxytocin is also involved in social cognition and social behaviour. Oxytocin receptors are also thought to be present in the hippocampus and amygdala, and the relationship between oxytocin and the structure and function of the hippocampus and amygdala has been reported. However, a few studies have investigated oxytocin and its relationship to hippocampus and amygdala volume in elderly people. The aim of this study is to investigate the association between serum oxytocin levels and hippocampus and amygdala volume in elderly people. The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 596 residents. Serum oxytocin level measurements, brain MRI, Mini–Mental State Examination and Clinical Dementia Rating were performed in Time 1 (2009–11). Follow-up brain MRI, Mini–Mental State Examination and Clinical Dementia Rating were performed in Time 2 (2016–17). The interval between Time 1 and Time 2 was about 7 years. Fifty-eight participants (14 men, mean age 72.36 ± 3.41 years, oxytocin 0.042 ± 0.052 ng/ml; 44 women, mean age 73.07 ± 4.38 years, oxytocin 0.123 ± 0.130 ng/ml) completed this study. We analysed the correlation between serum oxytocin levels (Time 1) and brain volume (Time 1, Time 2 and Times 1–2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping. Analysis at the cluster level (family-wise error; P < 0.05) showed a positive correlation between serum oxytocin levels (Time 1) and brain volume of the region containing the left hippocampus and amygdala (Time 2). This result suggests that oxytocin in people aged 65 years and older may be associated with aging-related changes in hippocampus and amygdala volume.

Low-grade inflammation is implicated in the pathogenesis of atherosclerosis, metabolic syndrome, and apathy as a form of vascular depression. We analyzed the brain magnetic resonance imaging findings in 259 community-dwelling older adults (122 men and 137 women, with a mean age of 68.4 years). The serum concentrations of high-sensitivity C-reactive protein (hsCRP) were measured by a quantitative enzyme-linked immunosorbent assay. Logistic regression analysis revealed that the log₁₀ hsCRP value and the presence of a metabolic syndrome were independently associated with confluent but not punctate deep white matter lesions (DWMLs). Path analysis based on structural equation modeling (SEM) indicated that the direct path from the log₁₀ hsCRP to the DWMLs was significant (β = 0.119, p = 0.039). The direct paths from the metabolic syndrome to the log₁₀ hsCRP and to the DWMLs were also significant. The direct path from the DWMLs to apathy (β = −0.165, p = 0.007) was significant, but the direct path from the log₁₀ hsCRP to apathy was not significant. Inflammation (i.e., elevated serum hsCRP levels) was associated with DWMLs independent of common vascular risk factors, while DWMLs were associated with apathy. The present analysis with SEM revealed the more realistic scheme that low-grade inflammation was associated with apathy indirectly via DWMLs in community-dwelling older adults.