Microglia respond to and induce anxiety and grooming in mice using calcium signaling.

Major depressive disorder (MDD), bipolar disorder (BD), schizoaffective disorder, and schizophrenia (SCZ) are conventionally defined categorical diagnoses, yet they share overlapping symptom domains and can be conceptualized along dimensions of affective psychopathology and psychosis [, ]. MDD is characterized primarily by persistent low mood and anhedonia, often precipitated by chronic stress or trauma [, ]. BD is defined by recurrent episodes of depression and mania/hypomania, frequently with mixed affective features, and psychotic symptoms in a substantial subgroup [, , ]. SCZ is characterized by hallucinations, delusions, disorganized thinking and cognitive impairments, with etiological contributions from neurodevelopmental and genetic risk factors [, ]. Across this affective–psychosis spectrum, immune-inflammatory alterations have been described in biologically distinct subgroups rather than uniformly at the diagnostic level [–], raising the possibility that microglial dysfunction may contribute to core symptom dimensions (e.g., depressive severity, psychosis burden, cognitive impairment) that cut across diagnostic boundaries [–]. While most reviews focus on a single disorder or methodology, this review integrates evidence across modalities that index complementary levels of microglia-related biology: translocator protein positron emission tomography (TSPO-PET; brain regional-level neuroimmune engagement in vivo), cerebrospinal fluid (CSF) profiling (soluble mediators and kynurenine (KYN) pathway balance in vivo), and postmortem studies (cellular phenotypes and regional enzyme/metabolite changes). Given that the extant human literature is predominantly organized around DSM/ICD diagnostic categories, our quantitative synthesis focuses on MDD and SCZ, with a supplementary PRISMA-guided qualitative synthesis of BD (due to the low number and heterogeneity of available BD studies). At the same time, we interpret diagnostic findings within an affective-psychosis spectrum-based and dimensional framework, emphasizing symptom- and subgroup-related moderators (e.g., suicidality, psychotic features, inflammatory subtypes) that are likely to contribute to inconsistency when heterogeneous clinical presentations are pooled under a single diagnostic label. Traditional models of MDD, BD and SCZ emphasized neuronal dysfunction, but growing evidence highlights the importance of glial cells [, ]. Microglia, the resident immune cells of the central nervous system (CNS), regulate synaptic plasticity, neurotransmission, neuroinflammation, and blood-brain barrier (BBB) integrity (Fig. ) [].