Abstract

Microglia, central immune and metabolic regulators, release metabolites that act as signaling molecules into the interstitial space within the neuro-immune-metabolic axis (NIMA). This review synthesizes evidence on how microglia-derived metabolites modulate neural circuit function—affecting synaptic plasticity, network oscillations, and behavior—and how their dysregulation contributes to psychiatric disorders. We highlight the dynamic role of the interstitial space in shaping metabolite signaling and discuss therapeutic strategies targeting this axis. Reconceptualizing microglial metabolites as active circuit modulators offers novel insights into psychiatric pathophysiology and potential metabolic interventions.

1 Introduction1.1 The global burden of psychiatric disorders and current therapeutic limitations

Psychiatric disorders represent a leading cause of disability and loss of life worldwide, imposing a tremendous public health burden (Yang et al., 2025). Major depressive disorder (MDD), affecting an estimated 280 million people globally with a lifetime prevalence of 10%–20% and a female-to-male ratio of approximately 2:1, stands as the foremost contributor to functional disability (Nayak et al., 2014; Yang et al., 2025). Schizophrenia (SZ), while less prevalent (∼0.3%–0.7%), typically manifests in adolescence or early adulthood and is associated with a 10–20-year reduction in life expectancy, conferring profound long-term impacts on patients, families, and society (Yang et al., 2025). Despite the partial efficacy of current therapies (e.g., antipsychotics, antidepressants), a substantial proportion of patients exhibit inadequate response or persistent core symptoms—particularly cognitive and negative symptoms—highlighting fundamental gaps in our understanding of their underlying pathophysiology (Chausse et al., 2021; Jauhar et al., 2022).

1.2 The emergence of a new paradigm and the core thesis of this review

This therapeutic impasse necessitates novel mechanistic frameworks. The integrated perspective of the “neuro-immune-metabolic axis (NIMA)” (Bohlen et al., 2017) has recently emerged as a transformative lens through which to re-examine psychiatric diseases (Bernier et al., 2020a,b). Within this framework, the role of microglia, the brain’s resident immune cells which constitute approximately 5%–10% of all cells in the central nervous system (Martins-Ferreira et al., 2025), is being fundamentally redefined: they are not merely immune sentinels but also active metabolic regulators and sources of signaling molecules (Bernier et al., 2020b; Erny et al., 2021; Liu and Zhou, 2024). This review posits a central thesis: under stress or pathological conditions, activated microglia undergo metabolic reprogramming, releasing a specific repertoire of metabolites—such as lactate, succinate, itaconate, and kynurenine. Critically, these molecules function not merely as metabolic waste or energy substrates but as novel chemical messengers. They are released into the brain’s dynamic interstitial space—a compartment far from being a passive conduit. Through dynamic fluctuations in its volume, composition, and diffusion properties, this space actively modulates the concentration, spatiotemporal range, and persistence of these signaling metabolites (Dogan et al., 2018; Holland et al., 2018; Hrabetova et al., 2018). Consequently, these microglia-derived metabolic signals directly regulate neuronal excitability, synaptic plasticity, and network oscillations, ultimately shaping behavioral outputs. Therefore, dysregulation of the “microglial metabolite–interstitial space–neural circuit” communication axis constitutes a pivotal mechanism driving neural circuit dysfunction in psychiatric disorders.

1.3 Review roadmap

We synthesize current knowledge on the generation, signaling mechanisms, circuit-level effects, and behavioral impacts of microglia-derived metabolites, as summarized in Figure 1, which provides a schematic overview of the NIMA linking microglial metabolites to neural circuits, behaviors, and psychiatric disorders. We further discuss their therapeutic potential in psychiatric diseases.

The neuro-immune-metabolic axis (NIMA): from microglial metabolites to circuit dysfunction and psychiatric disorders.

2 The microglial signaling metabolite repertoire2.1 Lactate2.1.1 Production, release, and epigenetic regulation

Upon neuroinflammatory activation, microglia undergo metabolic reprogramming characterized by a shift toward aerobic glycolysis (the Warburg effect), leading to substantial production and release of lactate (Pan et al., 2022). This lactate is shuttled into the interstitial space primarily via monocarboxylate transporters (MCTs) (Yang et al., 2025). Beyond serving as an energetic substrate, lactate functions as a signaling molecule capable of inducing histone lactylation—an emerging epigenetic modification that regulates the expression of immunometabolic and neuronal genes (Jiang et al., 2021; Zhang et al., 2019). In microglia, lactate-driven histone lactylation modulates transcriptional programs that influence inflammatory phenotype switching (Wang et al., 2019; Zhang et al., 2019). Thus, the cascade “inflammatory activation → glycolytic upregulation → lactate release → MCT-mediated transport → histone lactylation” constitutes a key mechanistic pathway linking microglial metabolism to epigenetic regulation in the brain.

2.1.2 Impact on neuronal function

Lactate fine-tunes neuronal activity through dual, often bidirectional, mechanisms: energy provision and receptor- or epigenetically-mediated signaling. As an energy substrate, lactate supports high-frequency network oscillations and sustains synaptic transmission during heightened neuronal activity (Tang et al., 2014). In parallel, lactate acts via specific receptors such as the hydroxycarboxylic acid receptor 1 (HCAR1) to modulate neuronal excitability (Lauritzen et al., 2014; Tang et al., 2014). Additionally, through histone lactylation, lactate regulates genes involved in synaptic plasticity and calcium homeostasis (Liu and Zhou, 2024; Wang et al., 2019). This dual role enables lactate to exert concentration-dependent effects on neural synchronization: physiological levels support gamma oscillations (γ-oscillations), whereas pathological accumulation can disrupt network activity by impairing mitochondrial function and interneuron performance (Zhang et al., 2023). Consequently, lactate serves as a critical metabolic signal that integrates energy metabolism with the dynamic regulation of neuronal excitability and synaptic efficacy.

2.2 Succinate2.2.1 Generation, accumulation, and core signaling mechanisms

Succinate, a key intermediate in the tricarboxylic acid (TCA) cycle, accumulates under conditions of inflammatory activation or mitochondrial dysfunction due to metabolic remodeling, primarily characterized by suppressed succinate dehydrogenase (SDH) activity (Tannahill et al., 2013). This accumulation triggers two core signaling pathways. Intracellularly, succinate competitively inhibits α-ketoglutarate-dependent prolyl hydroxylases (PHDs), leading to stabilization of hypoxia-inducible factor-1α (HIF-1α) and subsequent transcription of pro-inflammatory and glycolytic genes, such as IL-1β (Tannahill et al., 2013). Extracellularly, upon release into the interstitial space, succinate can act in a paracrine manner by activating the SUCNR1 (GPR91) receptor on neighboring microglia, neurons, and astrocytes (Jia and Wang, 2025; Peruzzotti-Jametti et al., 2018). SUCNR1 activation initiates Gαi/Gαq-mediated signaling, resulting in ERK1/2 phosphorylation, NF-κB activation, and calcium mobilization, thereby amplifying neuroinflammatory signaling (Macias-Ceja et al., 2019; Peruzzotti-Jametti et al., 2018; Rothhammer et al., 2018; Rubic et al., 2008).

2.2.2 Self-amplifying loops in neuroinflammation

Succinate potentiates neuroinflammatory responses through interconnected positive feedback loops that create a self-sustaining cycle (Maes et al., 2025). Intracellularly, HIF-1α stabilization not only promotes IL-1β expression but also enhances glycolytic flux, which can further contribute to succinate accumulation. Simultaneously, impaired SDH activity or reverse electron transport (RET) at mitochondrial complex II drives a burst of mitochondrial reactive oxygen species (mtROS) (Chahardehi et al., 2025; Mills et al., 2016; Weinberg and Chandel, 2025). This ROS surge activates the NLRP3 inflammasome, leading to caspase-1 activation and further maturation/secretion of IL-1β (Iwata et al., 2016; Maes et al., 2025). Extracellularly, SUCNR1 activation on immune cells stimulates additional release of inflammatory mediators like TNF-α (Li et al., 2024), which can in turn promote further succinate production and release from target cells. This vicious cycle—where succinate drives ROS and cytokine production, which then exacerbates succinate-associated signaling—chronically activates microglia and amplifies inflammatory cascades (Zhao et al., 2025). Ultimately, through sustained oxidative stress, pro-inflammatory cytokine toxicity, and disruption of metabolic homeostasis, this succinate-centered loop contributes significantly to synaptic dysfunction and neuronal damage, propagating neuropathology (Maes et al., 2025).

2.3 Itaconate2.3.1 Biosynthesis and core signaling mechanisms

Itaconate is an immunometabolite catalytically produced by ACOD1 (also known as IRG1) (Mills et al., 2018). It exerts potent anti-inflammatory and antioxidant effects through a dual core mechanism (Gao H. et al., 2025; Liu et al., 2025): (i) alkylation of KEAP1, which promotes Nrf2 stabilization and nuclear translocation to activate antioxidant transcriptional programs (Liu et al., 2025; Mills et al., 2018; Silva-Islas and Maldonado, 2018); and (ii) competitive inhibition of SDH, thereby reducing succinate accumulation, attenuating reverse electron transport (RET)-mediated mitochondrial reactive oxygen species (mtROS) generation, and dampening pro-inflammatory signaling (Gao H. et al., 2025; Lampropoulou et al., 2016; Mills et al., 2016). This positions itaconate as a key endogenous immunometabolic regulator (Moroni et al., 2012).

2.3.2 Neuroprotective potential

Through these dual pathways—activating the Nrf2-mediated antioxidant response and inhibiting SDH-driven pro-inflammatory signaling—itaconate downregulates key pro-inflammatory cytokines and promotes a metabolic shift in microglia, driving their transition from a pro-inflammatory toward a repair phenotype (Bambouskova et al., 2018; Chen Y. J. et al., 2023; Mills et al., 2018; Runtsch et al., 2022). This reprogramming helps restore redox homeostasis, limits NLRP3 inflammasome activation, and protects neuronal structure and synaptic function (Simpson et al., 2007), underscoring its therapeutic potential in neuroinflammatory contexts (Zheng et al., 2023).

2.4 Kynurenine2.4.1 Production, release, and core signaling mechanisms

The kynurenine pathway (KP) serves as a major route of tryptophan metabolism, primarily regulated by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) (Stone, 2001). Pro-inflammatory signals potently induce IDO, shifting metabolism toward the production of neuroactive metabolites that are released into the interstitial space (Brum et al., 2023; O’Connor et al., 2009; Schwarcz et al., 2012). The signaling function of this pathway hinges on two key metabolites with opposing actions on the N-methyl-D-aspartate (NMDA) receptor: kynurenic acid (KYNA), an endogenous NMDA receptor antagonist (Moroni et al., 2012), and quinolinic acid (QUIN), an NMDA receptor agonist (Schwarcz et al., 1983; Stone, 2001). The precise balance between KYNA and QUIN within the interstitial compartment acts as a critical metabolic switch, fine-tuning glutamatergic transmission and neuronal excitability (Schwarcz et al., 2012; Tan et al., 2012).

2.4.2 Impact on neuronal homeostasis and pathological imbalance

Physiologically, the equilibrium between KYNA and QUIN contributes to maintaining neuronal homeostasis, preventing both excessive excitation and insufficient glutamatergic tone (Stone, 2001). However, pathological disruption of this balance has significant consequences. A skew toward excess QUIN drives neuronal excitotoxicity and synaptic damage via sustained NMDA receptor overactivation, leading to calcium overload and oxidative stress (Behan et al., 1999; Cathomas et al., 2021). Conversely, elevated KYNA can induce glutamatergic hypofunction through excessive NMDA receptor blockade, thereby impairing synaptic plasticity and cognitive processes (Stachowski and Schwarcz, 2012; Stone, 2001). Thus, the KP constitutes a pivotal metabolic bridge linking immune activation to the precise regulation of central glutamatergic signaling and neuronal integrity (Table 1).

MetaboliteCore signaling mechanismsPrimary neural effectsPathophysiological roleLactate•HCAR1 activation
•Histone lactylation•Energy substrate and modulator of excitability
•Supports synaptic plasticity and gamma oscillationsHigh levels disrupt interneuron function and network synchrony (e.g., in Schizophrenia).Succinate•Intracellular: HIF-1α stabilization
•Extracellular: SUCNR1 activation•Amplifies pro-inflammatory responses (IL-1β)
•Drives mtROS and NLRP3 activationSustains vicious cycles of neuroinflammation, leading to synaptic damage (e.g., in MDD).Itaconate•KEAP1 alkylation → Nrf2 activation
•SDH inhibition•Potent anti-inflammatory and antioxidant
•Attenuates succinate-driven inflammationDeficient signaling exacerbates inflammation; its analogs hold therapeutic potential.Kynurenine pathway•Balance between QUIN (NMDA receptor agonist) and KYNA (NMDA receptor antagonist)•Fine-tunes glutamatergic transmission and excitabilityKYNA-dominant shift: NMDA receptor hypofunction (e.g., in Schizophrenia).
QUIN-dominant shift: excitotoxicity (e.g., in MDD).

Key signaling metabolites derived from microglia.

3 From molecules to circuits3.1 Coordinated regulation of synaptic plasticity and network oscillations

The metabolites discussed above do not act in isolation but constitute a dynamic regulatory network that operates in concert at both synaptic and network levels to shape neural circuit function. This integrated action can be conceptually organized into three functional modules: an energy and immediate signaling module (Yirmiya et al., 2015), an inflammation-excitotoxicity balancing module, and a protective and homeostatic restoration module. Together, these modules critically converge on two key circuit-level readouts frequently disrupted in psychiatric disorders: the excitation/inhibition (E/I) balance and the synchronization of neural networks, particularly γ-oscillations (30–40 Hz) which are essential for cognition and working memory.

3.1.1 Energy metabolism and immediate signaling module (lactate, adenosine)

This module provides the rapid bioenergetic and signaling foundation required to sustain high-frequency synaptic transmission and network synchrony. Lactate, shuttled from glycolytically active microglia and astrocytes via MCTs, serves a dual role as an energetic substrate for neurons and a signaling molecule (Liu and Zhou, 2024; Tang et al., 2014; Yang et al., 2025). It supports the metabolic demands of active neurons, thereby facilitating synaptic potentiation and sustaining high-frequency network activity. Furthermore, lactate potentiates NMDA receptor function, promoting synaptic plasticity and associated gene expression, partly through epigenetic mechanisms like histone lactylation (Liu and Zhou, 2024; Zhang et al., 2019). Its effects on γ-oscillations are concentration-dependent: physiological levels help maintain neural synchrony, while pathological accumulation can disrupt oscillations by impairing mitochondrial function, particularly in parvalbumin-positive (PV+) interneurons crucial for generating rhythmic activity (Yang et al., 2014; Zhang et al., 2019, 2023). Complementing lactate, adenosine—derived from activity-dependent hydrolysis of ATP—acts as an inhibitory balancer. It fine-tunes synaptic activity primarily through presynaptic A1 receptor-mediated suppression of glutamate release and modulation of NMDA receptor function (Huang et al., 2011; Porkka-Heiskanen et al., 1997). This purinergic signaling is vital for preventing network hyperexcitability, regulating sleep-wake cycles, and ensuring synaptic homeostasis. Together, lactate and adenosine form a metabolic-signaling duo that underpins the immediate energy supply and dynamic inhibition necessary for normal synaptic plasticity and oscillatory dynamics.

3.1.2 Inflammation-excitotoxicity balancing module (succinate, kynurenine pathway)

This module governs synaptic stability and survival by modulating the delicate equilibrium between neuroinflammation and excitatory tone. Succinate, a TCA cycle intermediate that accumulates during microglial activation or mitochondrial dysfunction, acts as a potent excitotoxicity and inflammation amplifier (Maes et al., 2025; Tannahill et al., 2013). Intracellularly, it stabilizes HIF-1α by inhibiting prolyl hydroxylases (PHDs), driving the expression of pro-inflammatory cytokines like IL-1β (Tannahill et al., 2013). Concurrently, it induces a burst of mitochondrial reactive oxygen species (mtROS) via reverse electron transport at SDH, further activating inflammatory cascades such as the NLRP3 inflammasome (Mills et al., 2016; Weinberg and Chandel, 2025). Extracellularly, succinate can engage the SUCNR1 receptor on neighboring cells, propagating pro-inflammatory signaling (Li et al., 2024; Peruzzotti-Jametti et al., 2018). The KP metabolites provide a complementary, bidirectional switch for glutamatergic transmission. The balance between its two key neuroactive products—QUIN (an NMDA receptor agonist) and KYNA (an NMDA receptor antagonist)—precisely tunes neuronal excitability and synaptic NMDA receptor function (Moroni et al., 2012; Stone, 2001; Tan et al., 2012). A pathological skew toward QUIN promotes excitotoxicity and calcium-mediated synaptic damage, while excess KYNA leads to NMDA receptor hypofunction, impairing synaptic plasticity (Schwarcz et al., 1983; Stachowski and Schwarcz, 2012; Stone, 2001). Thus, succinate and the KP converge on mechanisms involving oxidative stress, cytokine release, and NMDA receptor modulation to collectively determine synaptic fate—either supporting stability or driving degeneration.

3.1.3 Protection and homeostatic restoration module (itaconate, neuroactive steroids)

Acting as a crucial counter-regulatory axis, this module provides negative feedback to limit inflammatory and oxidative damage, thereby promoting repair and synaptic resilience. Itaconate, an immunometabolite synthesized by activated microglia via the enzyme ACOD1/Irg1, exerts potent anti-inflammatory and antioxidant effects (Liu et al., 2025; Mills et al., 2018). Its mechanisms are 2-fold: first, it alkylates KEAP1 to activate the Nrf2 pathway, leading to the upregulation of antioxidant genes; second, it competitively inhibits SDH, thereby reducing succinate accumulation and the associated mtROS production and NLRP3 inflammasome activation (Gao H. et al., 2025; Lampropoulou et al., 2016; Mills et al., 2016). Through these actions, itaconate downregulates pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and protects synaptic integrity. Neuroactive steroids, such as allopregnanolone, contribute to homeostasis by enhancing tonic inhibition via GABA_A receptor modulation, which can suppress microglial activation and constrain neuroinflammation, forming a stabilizing feedback loop (Marx et al., 2011; Pan et al., 2022). This module therefore restores redox balance, limits excitotoxic and inflammatory cascades, and creates a microenvironment conducive to synaptic recovery.

3.1.4 Integrated effects on E/I balance and gamma oscillations

The coordinated actions of these metabolic modules ultimately converge to regulate two fundamental and interconnected circuit properties: the E/I balance and the synchronization of γ-oscillations. The energy/inhibition module (lactate, adenosine) directly fuels and finely tunes the activity of interneurons, particularly PV+ cells, which are pivotal for generating gamma rhythms and maintaining inhibitory tone (Lewis et al., 2012; Zhang et al., 2023). Dysregulation here—such as pathological lactate accumulation impairing interneuron metabolism or aberrant adenosine signaling—can directly disrupt γ-oscillations and shift the E/I balance toward hyper- or hypo-excitability. Simultaneously, the inflammation-excitotoxicity module (succinate, KP) can indirectly degrade these circuit properties. By promoting oxidative stress, neuroinflammation, and aberrant NMDA receptor signaling, this module compromises the health and function of the very interneurons that sustain oscillations, while also altering glutamatergic synaptic weights, thereby destabilizing the E/I equilibrium (Maes et al., 2025; Steullet et al., 2016; Tannahill et al., 2013). Finally, the protective module (itaconate, neurosteroids) serves to buffer these disruptive processes, restoring homeostasis and preserving the functionality of the circuits underlying synchronized activity. Therefore, the NIMA, through the integrated and often opposing influences of its constituent metabolites, exerts precise control over synaptic plasticity and network synchrony. Disruption of this coordinated regulation represents a core mechanism underlying the circuit dysfunction observed across psychiatric disorders.

3.2 The interstitial space: a determinant of spatiotemporal specificity in metabolite signaling

The signaling functions of microglia-derived metabolites are not executed in a void but within the dynamic and structured interstitial space of the brain (Tønnesen et al., 2018; Xie et al., 2013). This compartment, far from being a passive gap, acts as a critical signaling hub whose biophysical properties fundamentally govern the spatiotemporal profile of metabolic communication, thereby filtering and shaping the functional outcomes on neural circuits and behavior.

3.2.1 Fundamental biophysical properties: diffusion, concentration, and signal lifetime

The interstitial space constitutes a fluid-filled network whose volume fraction and tortuosity determine the diffusion kinetics of signaling molecules (Syková and Nicholson, 2008; Xie et al., 2013). These physical parameters directly dictate a metabolite’s diffusion range, its achievable local concentration at target sites (e.g., synaptic clefts), and its functional lifetime before clearance (Hrabetova et al., 2018; Tønnesen et al., 2018). A smaller volume fraction or higher tortuosity restricts diffusion, leading to localized, high-concentration signaling niches. Conversely, a more open space facilitates broader dissemination but at potentially lower, sub-threshold concentrations. Thus, the interstitial architecture acts as a primary filter, selectively amplifying or attenuating microglial metabolic signals based on their molecular properties and the local extracellular geometry.

3.2.2 Dynamicity and brain-state dependency: the “accumulation-clearance” cycle

A pivotal feature of the interstitial space is its dynamic fluctuation, tightly coupled to brain states, most notably the sleep-wake cycle (Xie et al., 2013). During active wakefulness, neuronal and glial activity leads to a relative contraction of the interstitial volume. This contraction favors the local accumulation of signaling metabolites released by microglia and other cells, such as lactate, which can then reach effective concentrations to modulate synaptic plasticity and network oscillations (Dienel, 2019; Wyss et al., 2011). Conversely, during slow-wave sleep, the interstitial space expands significantly (Xie et al., 2013). This expansion dramatically enhances the convective bulk flow of interstitial fluid, facilitating the glymphatic clearance of metabolic waste products and potentially neurotoxic or pro-inflammatory substances that have accumulated during wakefulness (Nedergaard and Goldman, 2020). This includes excitatory metabolites like QUIN and pro-inflammatory signals like succinate (Hablitz et al., 2019; Savitz, 2020).

This rhythmic “diurnal accumulation-nocturnal clearance” cycle is crucial for brain homeostasis. It allows for the beneficial signaling functions of metabolites like lactate during cognitive demand while preventing the pathological buildup of excitotoxic and inflammatory mediators during rest. The dysregulation of this cycle is directly implicated in psychiatric symptomatology. For instance, chronic sleep disruption or stress can pathologically constrict the interstitial space (Koundal et al., 2020; Kress et al., 2014). This impairment hinders the clearance of metabolites such as succinate. The resulting abnormal accumulation sustains pro-inflammatory signaling via receptors like SUCNR1, a mechanism strongly associated with depressive-like phenotypes in preclinical models (Gao T. et al., 2025). This breakdown links directly to clinical features: impaired clearance during sleep leads to the persistence of neuroinflammatory and excitatory tones, contributing to the daytime fatigue, cognitive slowing, and maladaptive synaptic plasticity observed in disorders like major depression (Carrard et al., 2018; Savitz et al., 2015).

3.2.3 Regional heterogeneity: anatomical substrates for behavioral specificity

The properties of the interstitial space are not uniform across the brain, exhibiting significant regional heterogeneity in volume fraction, tortuosity, and the composition of the extracellular matrix (Hrabetova et al., 2018; Xie et al., 2013). This heterogeneity, combined with region-specific cellular metabolic demands and receptor expression patterns, creates distinct microenvironments that shape metabolite signaling. Consequently, identical amounts of a metabolite released by microglia can exert profoundly different effects in different brain circuits.

For example, the prefrontal cortex and the hippocampus display heightened sensitivity to lactate accumulation and KP dysregulation (Hagihara et al., 2018; Savitz et al., 2015). This regional vulnerability may stem from differences in interstitial architecture, local energy demands, or synaptic density, which affect metabolite diffusion and availability. Such specificity explains how metabolic disturbances can selectively impact circuits governing particular behaviors. Supporting this, spatial diffusion constraints significantly influence behavioral outcomes. In mice, the loss of microglial monocarboxylate transporter 4 (MCT4), a key lactate shuttling protein, leads to aberrant synaptic pruning and pronounced anxiety-like behaviors (Erblich et al., 2011; Sierra et al., 2014). This phenotype is likely due to disrupted lactate dynamics within the spatially constrained interstitial environment of prefrontal-limbic circuits, highlighting how the physical properties of the interstitial space gate the impact of metabolic signaling on specific behavioral domains like anxiety.

In summary, the interstitial space is a dynamic and heterogeneous regulator that confers spatiotemporal specificity to microglia-derived metabolite signals. Its physical properties control signal spread, its state-dependent volume changes enforce a vital clearance cycle, and its regional variability underlies the circuit- and behavior-specific effects of metabolic dysregulation. Disruptions at any level of this regulatory framework can drive the circuit dysfunction central to psychiatric disorders, making the interstitial space a critical conceptual and potential therapeutic node in the NIMA.

3.3 From dysregulated metabolic signaling to behavioral phenotypes

In summary, microglia-derived metabolites orchestrate higher-order cognitive and affective behaviors by fine-tuning neural circuit operations through the synergistic and spatiotemporally specific mechanisms described above. This regulation operates via a integrated “metabolite-interstitial space-circuit” signaling axis. Dysregulation of this axis manifests as three core behavioral pathological phenotypes: (Bohlen et al., 2017) cognitive impairments, such as deficits in working memory and executive function, linked to disrupted synaptic plasticity and network synchronization (e.g., aberrant γ-oscillations) (Lewis et al., 2012; Uhlhaas and Singer, 2010; Uhlhaas et al., 2008; Yang et al., 2025) affective dysregulation, including depression and anhedonia, associated with altered metabolite levels (e.g., lactate, KP metabolites) impacting prefrontal-limbic circuit integrity (Duman et al., 2016; Savitz et al., 2015; Savitz, 2020; Nayak et al., 2014) social dysfunction, arising from impaired microglial modulation of neural circuits governing social behavior (Zhan et al., 2014; Zhou et al., 2020). The following section will examine how disease-specific disruptions of particular metabolites selectively impair these related circuits, thereby giving rise to characteristic clinical symptom profiles in major psychiatric disorders.

4 Microglia-derived metabolites in major psychiatric disorders4.1 Schizophrenia4.1.1 Characteristic alterations in metabolite profiles

Patients with SZ exhibit distinct metabolic disturbances in key microglia-derived signaling molecules, particularly involving lactate and the KP. Multi-omics studies have demonstrated that lactate levels are significantly elevated in the cerebrospinal fluid and brain parenchyma of individuals with SZ (Prabakaran et al., 2004). This elevation exhibits a robust correlation with the severity of negative symptoms and treatment resistance (Dogan et al., 2018). Concurrently, dysregulation of the KP plays a pivotal role, with a characteristic shift toward the neuroprotective branch. In SZ, the pathway exhibits a predominant bias toward KYNA accumulation (Pocivavsek et al., 2014; Stachowski and Schwarcz, 2012). Elevated levels of KYNA in the brain interstitial space are posited to underpin the glutamatergic hypofunction hypothesis of the disorder (Comai et al., 2025). These alterations are not mere epiphenomena but are integral to the disease pathophysiology, directly contributing to the emergence of cognitive and affective symptoms by disrupting neural circuit function.

4.1.2 Mechanisms of circuit-level dysfunction

These metabolite imbalances drive neural circuit dysfunction through converging mechanisms that disrupt E/I balance and synaptic integrity. First, lactate accumulation, beyond its role as an energy substrate, may serve as a metabolic underpinning for aberrant γ-oscillations (Lewis et al., 2012; Liu and Zhou, 2024). PV+ interneurons, essential for generating synchronous gamma rhythms, are exquisitely sensitive to bioenergetic supply. Pathological lactate levels, potentially mediated through mechanisms such as impaired mitochondrial function or histone lactylation altering gene expression in these interneurons, can disrupt their fast-spiking activity (Marín, 2016; Prabakaran et al., 2004; Zhang et al., 2019). This impairs gamma oscillation generation, leading to desynchronization of prefrontal networks critical for working memory and contributing to the E/I imbalance observed in SZ (Foss-Feig et al., 2017; Steullet et al., 2016).

Second, the elevated KYNA levels directly impact synaptic plasticity and signal integration. By acting as an endogenous NMDA receptor antagonist, excessive KYNA exacerbates cortical glutamatergic hypofunction (Moroni et al., 2012; Stachowski and Schwarcz, 2012). This attenuates NMDA receptor-mediated currents, impairing mechanisms of synaptic plasticity such as long-term potentiation (LTP) that are fundamental for learning and cognitive function. The resultant dampening of glutamate signaling within prefrontal-limbic circuits disrupts information processing, contributing to the cognitive deficits and impaired executive function that are core features of SZ.

4.1.3 Link to clinical symptomatology

The circuit dysfunctions orchestrated by these metabolic disturbances provide a mechanistic scaffold for the diverse clinical symptoms of SZ. Cognitive symptoms, particularly working memory impairments, are strongly linked to the disruption of γ-oscillations and E/I imbalance caused by lactate-mediated interneuron dysfunction and KYNA-induced NMDA receptor hypofunction (Lewis et al., 2012; Uhlhaas and Singer, 2010; Uhlhaas et al., 2009). Negative symptoms (e.g., avolition, blunted affect) may arise from a generalized prefrontal cortical hypofunction, driven by the combined impact of impaired energy metabolism (lactate dysregulation) and reduced glutamatergic tone (KYNA excess), leading to decreased neural activity and drive (Dogan et al., 2018; McIntyre et al., 2020). Positive symptoms (e.g., hallucinations, delusions) may involve more distributed circuit disturbances. Dysfunctional gamma synchrony and E/I imbalance could disrupt the fidelity of signal transmission in cortical-thalamic and temporal-prefrontal circuits, potentially leading to aberrant assignment of salience and impaired reality monitoring, which are theorized to underlie psychotic phenomena (Uhlhaas and Singer, 2010; Uhlhaas et al., 2008). Thus, microglial metabolic reprogramming and the resultant interstitial metabolite profile act as a critical node, linking cellular pathology to the spectrum of circuit dysfunctions that manifest as the complex clinical picture of SZ.

4.2 Major depressive disorder4.2.1 Kynurenine pathway and glutamatergic toxicity

Dysregulation of the KP plays a central role in the pathophysiology of MDD. Under pro-inflammatory conditions, cytokines induce the enzyme IDO, shifting tryptophan metabolism toward the neurotoxic branch of the KP and promoting the production of QUIN over KYNA (Hughes et al., 2024; Stone, 2001). In MDD, the pathway is characteristically skewed toward QUIN accumulation (Hughes et al., 2024; Owe-Young et al., 2008; Savitz et al., 2015). Acting as an agonist at the NMDA receptor, elevated interstitial QUIN induces excitotoxicity, particularly within prefrontal-limbic circuits such as the hippocampus and amygdala (Roeske et al., 2021; Schwarcz et al., 1983). This excessive NMDA receptor activation leads to calcium overload, oxidative stress, and synaptic damage (Cathomas et al., 2021). The resultant impairment in synaptic plasticity within these emotion- and cognition-processing networks is strongly implicated in the core symptomatology of MDD, including deficits in emotional regulation and cognitive domains such as memory and executive function (Aarsland et al., 2017; Stone, 2001). Thus, the inflammation-driven shift toward QUIN generation establishes a direct metabolic link between peripheral immune activation and central glutamatergic dysfunction, underpinning key affective and cognitive symptoms of depression.

4.2.2 Succinate/itaconate and inflammatory loops

Neuroinflammation is a hallmark of MDD, wherein microglial-derived metabolites succinate and itaconate play opposing yet interconnected roles. Maes et al. (2025) propose succinate as a central node within the “inflammation-metabolism-mood disorder” axis implicated in depression. Under stress or inflammatory conditions, microglia undergo metabolic remodeling leading to succinate accumulation due to suppressed SDH activity (Tannahill et al., 2013). This accumulation triggers dual pro-inflammatory signaling: intracellularly, it stabilizes HIF-1α by inhibiting prolyl hydroxylases (PHDs), enhancing transcription of pro-inflammatory cytokines like IL-1β (Gao T. et al., 2025; Tannahill et al., 2013); extracellularly, it activates the SUCNR1 receptor on neighboring cells, further amplifying inflammatory cascades (Jia and Wang, 2025; Peruzzotti-Jametti et al., 2018). This process initiates a vicious cycle: succinate accumulation promotes mitochondrial ROS (mtROS) generation, which activates the NLRP3 inflammasome and upregulates IL-1β. This leads to sustained microglial activation, synaptic damage, dendritic spine loss, and a worsening of emotional and cognitive phenotypes (Mills et al., 2016; Schroder et al., 2010; Tannahill et al., 2013).