A systematic review of ketamine and esketamine-induced long-term potentiation and synaptic scaling: Do the molecular and synaptic plasticity effects inform dosing intervals?

The umbrella of synaptic plasticity includes associative, activity-dependent alterations in synaptic strength that are thought to underlie learning and memory, and negative feedback that stabilizes network activity, termed Hebbian and homeostatic plasticity, respectively. These forms of plasticity respond to activity oppositely, and on different spatial and temporal scales. However, despite these fundamental differences, many similar molecular mechanisms are engaged by each form of plasticity to alter synaptic strength. Here, we review molecular mechanisms involved in homeostatic plasticity and compare their involvement in Hebbian plasticity. We focus on synaptic scaling, long-term potentiation, and long-term depression, which are mediated by regulation of post-synaptic amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-type glutamate receptor (AMPARs) accumulation. Addressing synaptic scaffolding, intracellular signaling, cell-adhesion, and secreted factors, we identify mechanisms that appear to be convergent, differentially engaged, and divergent that uniquely regulate homeostatic scaling. These comparisons identify clear gaps to be addressed by future studies that aim to parse the contributions of Hebbian and homeostatic plasticity to regulate AMPAR function.

Environmental light significantly influences neural development, yet the specific mechanisms underlying the effects of prolonged visual experience on homeostatic synaptic scaling remain unclear. Using manipulated ambient light conditions, we observed reduced mEPSC amplitudes and visually evoked responses in 20 hr light/4 hr dark (20LE) compared to a standard 12 hr light/12 hr dark (12LE) reared Xenopus laevis tadpoles. Prolonged light exposure accelerates the developmental decline of glutamatergic synaptic transmission via Rab5c-dependent endocytosis of AMPA receptor (AMPAR) subunits GluA1 and GluA2. The synaptic changes were accompanied by increased intrinsic neuronal excitability, but unchanged presynaptic release probability, and coincided with altered dendritic architecture. Notably, synaptic transmission and AMPAR expression were reversible upon re-exposure to standard 12LE conditions. Class I HDAC-mediated histone acetylation links epigenetic regulation to sustained AMPAR downregulation, revealing a two-stage process in which prolonged visual experience drives homeostatic synaptic downscaling through coordinated transcriptional/epigenetic mechanism and Rab5c-mediated trafficking.

ABSTRACTThe mechanistic target of Rapamycin (mTOR) kinase pathway plays critical roles in neuronal function and synaptic plasticity, and its dysfunction is implicated in numerous neurological and psychiatric disorders. Traditional linear models depict mTOR signaling as a sequential phosphorylation cascade, but accumulating evidence supports a model that includes signaling through dynamic protein–protein interaction networks. To examine how neuronal mTOR signaling networks discriminate between distinct stimuli, we quantified phosphorylation events and protein co‐association networks in primary mouse cortical neurons. Unexpectedly, neuronal mTOR activation by IGF or glutamate triggered dissociation—rather than the anticipated assembly—of protein complexes involving mTOR complex 1 (TORC1), mTOR complex 2 (TORC2), and translational machinery, distinguishing neurons from proliferative cells. Applying in vitro homeostatic scaling paradigms revealed distinct combinatorial encoding of synaptic scaling direction: both up‐ and down‐scaling induced dissociation of translational complexes, but downscaling uniquely included dissociation of upstream pathway regulators. Cortical neurons from Shank3B knockout mice, modeling autism‐associated Phelan‐McDermid Syndrome, displayed baseline hyperactivation of the mTOR network, which reduced the dynamic range of protein interaction network responses to homeostatic synaptic scaling and pharmacological mTOR inhibition. These findings reveal that neuronal mTOR signaling employs stimulus‐specific combinations of dissociative protein interaction modules to encode opposing forms of synaptic plasticity.

Maintaining appropriate behavioral and physiological responses in the face of challenge is essential for survival. The persistent increase in corticosteroids (CORT) during chronic stress blunts the endocrine response to any subsequent stressors. But the impact of prolonged CORT on behaviors that promote survival in the face of an acute stress is not well understood. Here we used an aerial predator threat model combined with in vivo calcium imaging, whole-cell electrophysiology, chemogenetics and computational modeling to evaluate the effects of short and long-term CORT. We show that in the short term, the activity of the corticotropin releasing hormone neurons of the paraventricular nucleus of the hypothalamus (CRHPVN) and innate defensive behaviors that rely on these cells, are sensitive to the negative feedback effects of CORT. In response to long-term increases in CORT, however, behaviors recover, even though intrinsic CRHPVN activity remains low. This escape from negative feedback requires local, homeostatic scaling of glutamate synapses that overcomes the inhibitory effects of CORT. This scaling is sufficient to maintain the output of this system in vivo and preserves innate defensive responses to threat. We propose that homeostatic synaptic scaling functions as a local adaptive mechanism to preserve the reliability of essential survival circuits during times of chronic stress.

The SNX27-Retromer and more recently discovered SNX17-Retriever complexes are key drivers in recycling internalized cargoes back to the cell surface in eukaryotic cells, but the extent to which these pathways have unique or redundant roles in neurons is not known. Here, we show similar, but non-overlapping, roles of the SNX17-Retriever and SNX27-Retromer pathways in the maintenance and plasticity of excitatory synapses. We find that in vivo disruption of either pathway in developing rats leads to a marked loss of excitatory synapses in CA1 pyramidal neurons, a phenotype that is recapitulated in cultured hippocampal neurons. Further analysis in cultured neurons confirms that SNX17 and SNX27 colocalize prominently with each other and Retriever/Retromer in early endosomes, indicating a largely shared cellular localization of the two pathways. Interestingly, coordinate disruption of both pathways produced an additive loss of excitatory synapses, suggesting parallel roles in synapse maintenance. We further show that certain cargoes are specific for each pathway and that both recycling pathways are essential for numerous forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic synaptic scaling. Together, our results support a model where the SNX17-Retriever and SNX27-Retromer pathways function largely in parallel at synapses, with their combinatorial action a key requirement for long-lasting forms of synaptic plasticity.

Elucidating the impact of aging on the structure and function of neurons is key to understanding the mechanisms underlying synaptic dysfunction and ensuing susceptibility to age-related cognitive decline. The role of structural alterations in the lateral prefrontal cortex (LPFC) has been extensively addressed. In addition, numerous studies point to the importance of inflammation and the increase of oxidative stress during aging, with mitochondria as one of the key cellular organelles involved. Here, we used 3D high-resolution serial block-face scanning electron microscopy to visualize the ultrastructure of synapses on pyramidal neurons in area 46 of the LPFC in rhesus monkeys at different stages across their adult lifespan. Our results revealed a general loss of synapses with age, mainly driven by the loss of asymmetric axospinous synapses. We observed a larger bouton volume but not larger spine or postsynaptic density (PSD) surface in the aged group compared to all other groups, along with a weaker correlation between spine and synaptic size. Additionally, we found morphological changes in mitochondria in the aged compared to middle-aged and young monkeys. Altogether, our data show ultrastructural changes that suggest an improper synaptic scaling and possible mitochondrial dysfunction that might take place after middle-age. We studied the impact of curcumin as a long-term dietary supplement and found that it ameliorated some of these age-related changes at middle-age by preserving the spine and PSD morphology and their size relationship, and also mitochondrial morphology, which might allow for maintaining synaptic function during aging, resulting in a delayed cognitive decline.

Tumor cell plasticity in novel microenvironments is central to the integration and subsequent growth of metastatic cells. However, the functional consequences of tumor cell integration with central neurons remains understudied. Here, we address this question using small cell lung cancer (SCLC), which has an extraordinary propensity to metastasize to the brain in humans. Transcriptomic and electrophysiological analysis of SCLC cells in neuronal microenvironments reveal a heterogeneous population of synapse-forming SCLC cells with neurons. While a proportion of neuron-SCLC synapses are blocked by AMPA receptor antagonists, we also find a sensitivity of these synapses to GABAA receptor inhibition. The functional integration of SCLC with central neurons induced multiplicative synaptic upscaling between neurons and dysregulated neuronal excitability. Aberrant excitation in human neurons with SCLC was sustained by synaptic NMDA receptor activation and can be reduced by the FDA approved NMDA receptor blocker memantine. These findings reveal strategies to normalize tumor-induced exacerbation of aberrant neuronal activity.

In primary visual cortex (V1), neuronal receptive fields are generally thought to be fully established prior to eye-opening, with subsequent experience-dependent refinement controlled by GABAergic inhibition and regulated by homeostatic mechanisms. However, GABAergic interneurons (INs) are diverse and relatively little is known about the early postnatal roles of dendrite-targeting interneurons. Surprisingly, we find that somatostatin-expressing interneurons (SST-INs) in mouse V1 are not visually responsive at eye opening, instead developing visual sensitivity during the third postnatal week. Over the same period, SST-INs exhibit a rapid increase in excitatory innervation without compensatory synaptic scaling. Simultaneous imaging and optogenetic manipulation in juvenile animals reveals that SST-INs largely exert a multiplicative modulation of nearby excitatory neuron responses at all ages, but this effect increases over time. Our results identify a uniquely delayed developmental window for maturation of this inhibitory circuit and its contribution to visual gain normalization.

Nervous systems utilize temporally precise patterns of activity. However, the mechanisms by which spike patterns are processed are not known. In particular, the fact that during learning different patterns are distributed over time raises the question of how groups of neurons become selective for new spike patterns without overwriting already learned patterns. A simple one-layer spiking neural network model is presented that learns to recognize spatiotemporal spike patterns sequentially. The approach integrates biological synaptic mechanisms, including Hebbian learning, heterosynaptic plasticity, and synaptic scaling, allowing groups of neurons to self-organize selectivity for a set of spike patterns. Spoken words, transformed by a cochlear model into spatio-temporal spike patterns, are learned without supervision. This work suggests how the brain can use temporal spike codes and provides a novel, scalable, efficient, and noise-tolerant solution to the stability-plasticity dilemma.

Shank3 is an autism spectrum disorder-associated postsynaptic scaffold protein that links glutamate receptors to trafficking and signaling networks within the postsynaptic density. Shank3 is required for synaptic scaling, a form of homeostatic plasticity that bidirectionally modulates postsynaptic strength to stabilize neuronal activity. Shank3 undergoes activity-dependent phosphorylation/dephosphorylation at S1586/S1615, and dephosphorylation at these sites is critical for enabling synaptic upscaling. Here, we probe the molecular machinery downstream of Shank3 dephosphorylation that allows for synaptic upscaling in cultured rat neurons of either sex. We first show that a phosphomimetic mutant of Shank3 has reduced binding ability and interaction with long-form Homer1, a postsynaptic protein also crucial for scaling and a known binding partner of Shank3. Since metabotropic glutamate receptor 5 (mGluR5) has been shown to associate with Shank3 through long-form Homer1, we manipulated mGluR1 and mGluR5 signaling with either noncompetitive or competitive inhibitors and found that only competitive inhibition (which targets agonist-dependent signaling) impairs synaptic upscaling. Furthermore, we found that mGluR5 activation rescues synaptic upscaling in the presence of phosphomimetic Shank3 and thus is downstream of Shank3 phosphorylation. Finally, we identify signaling pathways downstream of Group I mGluRs that are necessary for upscaling. Altogether, these data show that activity-dependent dephosphorylation of Shank3 remodels the Shank3/Homer1/mGluR signaling pathway to favor agonist-dependent mGluR signaling, which is necessary to enable synaptic upscaling. More broadly, because downscaling is thought to require agonist-independent mGluR5 signaling, these findings demonstrate that synaptic up- and downscaling rely on distinct functional configurations of the same signaling elements.

CBF gradient and excitatory-inhibitory balance measured from pre-SMA - importance in aging and semantic fluency task difficulties.

Cholecystokinin (CCK) is the most prevalent neuropeptide in the brain, where it affects satiety, pain modulation, memory, and anxiety. Its effects are mediated by GPCRs known as the “alimentary (gastrointestinal)” CCK1r (CCK 1 receptor) and the brain-specific CCK2r (CCK 2 receptor). While stress causes CCK to be released and full CCK2r agonists are potent panicogenic agents, specific CCK2r antagonists are ineffective at lowering human anxiety. As a result, the therapeutic potential of CCK as a target in psychiatry has been questioned. By compiling relevant new and historical scientific data retrieved from Scopus and PubMed, the aim of this review was to suggest a new function of CCK neurotransmission, the regulation of neuronal homeostasis during stress. Four lines of evidence were discussed that support the hypothesis of a CCK-driven neuronal homoestasis: (1) Homeostatic plasticity including synaptic scaling and intrinsic excitability; (2) its interaction with retrograde endocannabinoid signaling; (3) neuroprotective role; and (4) dynamic neuromodulation of CCK release. CCK functions as a crucial and essential molecular switch of neural circuits and neuroplasticity through its remarkable cell-specific modulation of glutamate and GABA release via CCK2r. CCKergic neurons are downstream of the activation of cannabinoid type-1 (CB1) receptors in order to generate and stabilize rhythmic synchronous network activity in the hippocampus. CCK is also released to modulate other neurotransmitters like dopamine and opioids when neuronal firing is intense during the processing of anxiety/fear, memory, and pain. CCK likely functions to restore baseline neuronal function and protect neurons from harm under these conditions. Anxiety, depression, and schizophrenia could result from compensatory plastic changes of the CCKergic system that go awry during neuronal homeostasis. This review concludes by examining the benefits of putative compounds that exhibit a combination of CCK agonist and antagonist activity at multiple locations within the CCKergic system, as well as off-targets in managing mental conditions.

ABSTRACT Homeostatic synaptic plasticity is essential for maintaining stable neural circuit function by preventing excessive neuronal excitation or inhibition. Chronic perturbation of neuronal activity triggers a compensatory modulation of the number of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors at the excitatory synapses. Previous research has primarily focused on AMPA receptors, yet the molecular mechanisms regulating the trafficking of NMDA receptors during homeostatic synaptic scaling remain unclear. Here we identify the microtubule-associated protein Tau as an essential molecule that mediates the synaptic upscaling of GluN2B-containing NMDA receptors during prolonged synaptic inactivity. Chronic activity blockade increases Tau phosphorylation at Ser-235 by cyclin-dependent kinase 5 (Cdk5), enhancing its interaction with and retention of active Fyn tyrosine kinase in the postsynaptic compartment. This promotes the phosphorylation of GluN2B at Tyr-1472, subsequently stabilising the expression of NMDA receptors on the neuronal plasma membrane. Finally, we showed that Tau pathology and disease-associated mutations in Tau and the GluN2B carboxyl-terminal tail disrupt the homeostatic synaptic upscaling of NMDA receptors following chronic neuronal silencing. Together, our findings identify a physiological role for Tau in homeostatic synaptic plasticity, the perturbation of which can lead to neuronal hyperexcitation, seizures and excitotoxic cell death.

Copy number deletions in the 2p16.3/NRXN1 locus confer genome wide risk for autism spectrum disorder (ASD) and schizophrenia (SCZ). Prior work demonstrated that heterozygous NRXN1 deletions decreases synaptic strength and neurotransmitter release probability in human-iPSC derived cortical glutamatergic induced neurons and this synaptic phenotype is replicated in SCZ patient iPSCs with varying NRXN1 genomic deletions. What is unknown, however, is whether similar synaptic impairment exists in ASD patients carrying NRXN1 deletions. Answering this question is important to determine whether all NRXN1 deletion carriers should be treated similarly or individually, based on their genetic backgrounds and deletion breakpoints. Here, using previously uncharacterized ASD patient iPSC lines, we show that ASD-NRXN1 deletions impact cortical synaptic function and plasticity in unique ways compared to SCZ-NRXN1 deletions. Specifically, at a single neuronal level, ASD-NRXN1 deletions alter basal spontaneous synaptic transmission by selectively enhancing excitatory synaptic signaling with no changes at inhibitory synapses while SCZ-NRXN1 deletions reduce both excitatory and inhibitory synaptic transmission. At the neuronal network level, there exists enhanced transmission probability and irregular firing patterns in ASD-NRXN1 deletions. Such changes at the synaptic and network level connectivity patterns influence a critical form of developmental cortical plasticity, synaptic scaling, as ASD-NRXN1 deletions uniquely fail to upscale their synaptic strength in response to chronic neuronal silencing. Together, these findings highlight the disorder-specific consequences of NRXN1 deletions on synaptic function and connectivity, offering mechanistic insights with implications for therapeutic targeting and refinement strategies for NRXN1-associated synaptopathies.

Haploinsufficiency disorders are genetic diseases caused by reduced gene expression, leading to developmental, metabolic, and tumorigenic abnormalities. The dosage-sensitive Retinoic Acid Induced 1 (RAI1) gene, located within the 17p11.2 region, is central to the core features of Smith--Magenis syndrome (SMS) and Potocki--Lupski syndrome (PTLS), caused by the reciprocal microdeletions and microduplications of this region, respectively. SMS and PTLS present contrasting phenotypes. SMS is characterized by severe neurobehavioral manifestations, sleep disturbances, and metabolic abnormalities, and PTLS shows milder features. Here, we detail the molecular functions of RAI1 in its wild-type and haploinsufficiency conditions (RAI1+/-), as studied in animal and cellular models. RAI1 acts as a transcription factor critical for neurodevelopment and synaptic plasticity, a chromatin remodeler within the Histone 3 Lysine 4 (H3K4) writer complex, and a regulator of faulty 5'-capped pre-mRNA degradation. Alterations of RAI1 functions lead to synaptic scaling and transcriptional dysregulation in neural networks. This review highlights key molecular mechanisms of RAI1, elucidating its role in the interplay between genetics and phenotypic features and summarizes innovative therapeutic approaches for SMS. These data provide a foundation for potential therapeutic strategies targeting RAI1, its mRNA products, or downstream pathways.

Critical network states and neural plasticity enable adaptive behavior in dynamic environments, supporting efficient information processing and experience-dependent learning. Synaptic-weight-based Hebbian plasticity and homeostatic synaptic scaling are key mechanisms that enable memory while stabilizing network dynamics. However, the role of structural plasticity as a homeostatic mechanism remains less consistently reported, particularly under activity inhibition, leading to an incomplete understanding of its functional impact. In this study, we combined live-cell microscopy of eGFP-labeled neurons in mouse organotypic entorhinal-hippocampal tissue cultures (Thy1-eGFP mice of both sexes) with computational modeling to investigate how synapse-number-based structural plasticity responds to activity perturbations and interacts with homeostatic synaptic scaling. Tracking individual dendritic segments, we found that inhibiting excitatory neurotransmission does not monotonically regulate dendritic spine density. Specifically, inhibition of AMPA receptors with 200 nM 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) increased spine density, whereas complete AMPA receptor blockade with 50 μM NBQX reduced it. Motivated by these findings, we developed network simulations incorporating a biphasic structural plasticity rule governing activity-dependent synapse formation. These simulations showed that the biphasic rule maintains neural activity homeostasis under stimulation and permits either synapse formation or synapse loss depending on the degree of activity deprivation. Homeostatic synaptic scaling further modulated recurrent connectivity, network activity, and structural plasticity outcomes. It reduced stimulation-triggered synapse loss by downscaling synaptic weights and rescued silencing-induced synapse loss by upscaling recurrent input, thus reactivating silent neurons. The interaction between these mechanisms provides a mechanistic explanation for divergent findings in the literature. In summary, homeostatic synaptic scaling and homeostatic structural plasticity dynamically compete and compensate for each other, ensuring efficient and robust control of firing rate homeostasis.

Critical network states and neural plasticity enable adaptive behavior in dynamic environments, supporting efficient information processing and experience-dependent learning. Synaptic-weight-based Hebbian plasticity and homeostatic synaptic scaling are key mechanisms that enable memory while stabilizing network dynamics. However, the role of structural plasticity as a homeostatic mechanism remains less consistently reported, particularly under activity inhibition, leading to an incomplete understanding of its functional impact. In this study, we combined live-cell microscopy of eGFP-labeled neurons in mouse organotypic entorhinal-hippocampal tissue cultures (Thy1-eGFP mice of both sexes) with computational modeling to investigate how synapse-number-based structural plasticity responds to activity perturbations and interacts with homeostatic synaptic scaling. Tracking individual dendritic segments, we found that inhibiting excitatory neurotransmission does not monotonically regulate dendritic spine density. Specifically, inhibition of AMPA receptors with 200 nM 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) increased spine density, whereas complete AMPA receptor blockade with 50 μM NBQX reduced it. Motivated by these findings, we developed network simulations incorporating a biphasic structural plasticity rule governing activity-dependent synapse formation. These simulations showed that the biphasic rule maintains neural activity homeostasis under stimulation and permits either synapse formation or synapse loss depending on the degree of activity deprivation. Homeostatic synaptic scaling further modulated recurrent connectivity, network activity, and structural plasticity outcomes. It reduced stimulation-triggered synapse loss by downscaling synaptic weights and rescued silencing-induced synapse loss by upscaling recurrent input, thus reactivating silent neurons. The interaction between these mechanisms provides a mechanistic explanation for divergent findings in the literature. In summary, homeostatic synaptic scaling and homeostatic structural plasticity dynamically compete and compensate for each other, ensuring efficient and robust control of firing rate homeostasis.

Critical network states and neural plasticity enable adaptive behavior in dynamic environments, supporting efficient information processing and experience-dependent learning. Synaptic-weight-based Hebbian plasticity and homeostatic synaptic scaling are key mechanisms that enable memory while stabilizing network dynamics. However, the role of structural plasticity as a homeostatic mechanism remains less consistently reported, particularly under activity inhibition, leading to an incomplete understanding of its functional impact. In this study, we combined live-cell microscopy of eGFP-labeled neurons in mouse organotypic entorhinal-hippocampal tissue cultures (Thy1-eGFP mice of both sexes) with computational modeling to investigate how synapse-number-based structural plasticity responds to activity perturbations and interacts with homeostatic synaptic scaling. Tracking individual dendritic segments, we found that inhibiting excitatory neurotransmission does not monotonically regulate dendritic spine density. Specifically, inhibition of AMPA receptors with 200 nM 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) increased spine density, whereas complete AMPA receptor blockade with 50 μM NBQX reduced it. Motivated by these findings, we developed network simulations incorporating a biphasic structural plasticity rule governing activity-dependent synapse formation. These simulations showed that the biphasic rule maintains neural activity homeostasis under stimulation and permits either synapse formation or synapse loss depending on the degree of activity deprivation. Homeostatic synaptic scaling further modulated recurrent connectivity, network activity, and structural plasticity outcomes. It reduced stimulation-triggered synapse loss by downscaling synaptic weights and rescued silencing-induced synapse loss by upscaling recurrent input, thus reactivating silent neurons. The interaction between these mechanisms provides a mechanistic explanation for divergent findings in the literature. In summary, homeostatic synaptic scaling and homeostatic structural plasticity dynamically compete and compensate for each other, ensuring efficient and robust control of firing rate homeostasis.

Beyond their role in immune signaling, cytokines have emerged as key neuromodulators that influence processes including neurotransmitter function, neuronal excitability, synaptic plasticity, neurogenesis, myelination, and cortical sleep state. These roles are observed in the healthy brain and during infections when they reorient motivational, cognitive, and emotional responses. Experimental evidence from human and nonhuman primate immune challenge studies has been pivotal to understanding these effects. By showing that elevated cytokines readily induce transdiagnostic symptoms, including anhedonia, social withdrawal, psychomotor slowing, and cognitive impairment, these studies have also helped demonstrate that inflammation contributes to the shared neural dysfunction observed across psychiatric and neurological disorders. Cytokines modulate glutamatergic and GABAergic (gamma-aminobutyric acidergic) neurotransmission, impair dopaminergic and serotonergic signaling, and regulate homeostatic synaptic scaling, leading to altered network connectivity and behavioral deficits. While research has often focused on single cytokines in isolation, neuroimmune signaling occurs through combinatorial cytokine codes, requiring systems-level approaches to understand their interactive effects. Advances in neuroimaging, molecular neuroscience, and biophysical modeling offer opportunities to link cellular cytokine action with macroscale network dysfunction, enabling mechanistic insights into cytokine-mediated neuromodulation. Clinically, cytokine-targeting therapies hold promise for treating inflammation-driven cognitive and mood disorders, but their long-term impact on neuroplasticity remains uncertain. Future research should characterize immune signatures predictive of neuropsychiatric symptoms, identify cell type-specific cytokine effects, and integrate multiscale modeling to refine understanding of neuroimmune interactions. Reconceptualizing cytokines as fundamental regulators of neural function rather than merely inflammatory mediators is crucial for developing precision medicine to mitigate immune-driven brain dysfunction and improve mental health outcomes.