1. Introduction
Microglia, the CNS’s resident immune cells, are indispensable for brain development, regulating synaptic pruning, neurogenesis, and immune responses. Their activity aligns with developmental stages such as embryogenesis, synaptogenesis, and adolescence, making these periods particularly vulnerable to dysfunction [1]. During synaptogenesis, microglia refine neural circuits, while in adolescence, they maintain synaptic plasticity. Disruptions during these windows contribute to pediatric conditions like ASD and epilepsy [2]. This review highlights the molecular underpinnings of microglial dysfunction, therapeutic strategies, and future research directions, with a focus on age-specific vulnerabilities.
2. Microglial Functions in Normal Brain Development
Microglia play stage-specific roles throughout development. During embryogenesis, they regulate neurogenesis by releasing growth factors like IGF-1 and BDNF, supporting neural progenitor cell survival and differentiation [3]. During early postnatal periods, microglia mediate synaptic pruning by recognizing complement proteins such as C1q via CR3 receptors, ensuring proper circuit refinement [4]. Dysregulation in these processes leads to altered connectivity, as seen in ASD. Microglial plasticity enables them to adapt dynamically to the needs of the developing brain, ensuring proper neural homeostasis. However, dysregulation of this plasticity can lead to pathological outcomes, such as altered synaptic connectivity and immune responses [5].
As the brain matures, microglia transition from trophic roles to immune surveillance. For example, in adolescence, microglia maintain synaptic plasticity but also shift toward a pro-inflammatory state, increasing vulnerability to neuroinflammation and injury [6]. Additionally, microglia engage in synaptic stripping, a process essential for remodeling neural circuits during development. This highlights their dual role in maintaining synaptic plasticity and immune regulation [7].
Figure 1. Microglial contributions to pediatric neurological disorders.
Microglia are depicted performing key roles in neural homeostasis (see Figure 1). These include synaptic pruning, critical for refining neural circuits; supporting neurogenesis through growth factor release; and clearing apoptotic cells to maintain a healthy brain environment. Arrows indicate interactions with synapses and apoptotic cells. Adapted from Reference [8].
3. Microglia in Specific Pediatric Neurological Disorders
Microglia in Autism Spectrum Disorder (ASD)
ASD involves neuroinflammation, with postmortem studies showing increased microglial activation in the prefrontal cortex and cerebellum [9]. Overactivation of microglia can lead to excessive synaptic pruning, disrupting the excitation-inhibition balance essential for normal cortical function [10]. Molecular pathways such as mTOR and NF-κB are implicated in this process, driving cytokine release and neuroinflammatory cascades [11]. Microglia also act as neuroimmune sensors, adapting their function in response to stress. Chronic stressors can shift microglia toward a pro-inflammatory phenotype, potentially exacerbating neuroinflammation and impairing neural development during critical periods [12].
Emerging evidence from primary studies highlights microglial compensatory mechanisms. For instance, Reference [13] demonstrated that impairments in neuron-microglia signaling via the CX3CL1/CX3CR1 axis exacerbate social deficits in ASD models. Clinical trials are underway to evaluate anti-inflammatory agents like ibudilast for their potential to modulate microglial activation in ASD.
Microglia in Pediatric Epilepsy
Epilepsy, affecting over 470,000 children in the U.S., involves neuroinflammation driven by microglial activation. Pro-inflammatory cytokines such as IL-1β and TNF-α disrupt neuronal homeostasis, promoting hyperexcitability and seizure propagation [14]. Receptors for advanced glycation end-products (RAGE) are significantly upregulated in epilepsy, driving neuroinflammatory responses that amplify seizure activity and neuronal damage [15]. Microglial depletion using CSF1R inhibitors, such as PLX5622, has been shown to reduce seizure severity in rodent models [13].
The JAK/STAT pathway has emerged as a key driver of microglial-mediated neuroinflammation in epilepsy, offering a promising therapeutic target. Ongoing clinical trials, including investigations of IL-1 receptor antagonists (anakinra), aim to assess their efficacy in pediatric drug-resistant epilepsy populations.
1) Microglia in Childhood-Onset Neurodegenerative Diseases
Childhood neurodegenerative disorders such as Rett syndrome and juvenile Huntington’s disease involve distinct microglial dysfunctions. In Rett syndrome, MECP2 mutations impair microglial phagocytosis, reducing synaptic maintenance and increasing neuronal apoptosis [16]. Wild-type microglial transplantation has shown partial restoration of normal neuronal function, suggesting a therapeutic pathway [17]. Additionally, microglia play a critical role in innate immunity by clearing amyloid plaques and maintaining neural health. Dysregulation of this process can exacerbate neurodegenerative progression, as seen in juvenile conditions [18].
Conversely, juvenile Huntington’s disease involves early microglial overactivation, driven by dysregulated CX3CL1 signaling, which accelerates neuronal loss in the striatum [19].
Microglial activation pathways in autism spectrum disorder (ASD), epilepsy, and neurodegenerative diseases are shown (see Figure 2). Key mechanisms include cytokine release, neuroinflammation, and hyperexcitability. Specific microglial interactions in disease pathology, such as synaptic dysfunction in ASD and inflammatory cascades in epilepsy, are illustrated. Adapted from Reference [9], and Reference [20].
Figure 2. Microglial functions across neural processes.
4. Age-Dependent Microglial Responses and Implications for Pediatric Neurology
Microglia exhibit dynamic functional changes across developmental stages, which significantly influence their roles in pediatric neurological disorders. During early life, microglia predominantly adopt an anti-inflammatory phenotype, supporting neurogenesis, synaptic pruning, and immune regulation [1]. For example, neonatal microglia facilitate synaptic refinement via complement signaling, ensuring the proper establishment of neural circuits [4].
In adolescence, microglia transition to maintaining synaptic plasticity and homeostasis, a process regulated by signaling pathways such as CX3CL1/CX3CR1. However, this transition also makes microglia more reactive to inflammatory stimuli, which can exacerbate neuroinflammatory responses [6]. For instance, microglial responses to febrile seizures in early childhood involve greater synaptic remodeling than those observed in adult epilepsy, highlighting developmental differences in microglial activation [21].
Recent studies suggest that developmental stage-specific microglial responses are mediated by shifts in gene expression and signaling networks. For example, transcription factors like IRF8 and PU.1 regulate microglial activation states, with IRF8 associated with pro-inflammatory responses in maturing microglia [2]. Dysregulation of these factors during critical windows can lead to long-term neurodevelopmental consequences, such as those observed in ASD and epilepsy.
The implications for pediatric neurology are profound. Interventions targeting microglial activity must consider age-dependent shifts to avoid unintended effects. For example, while anti-inflammatory therapies may be effective in adolescence, they could disrupt essential microglial functions in early development. The timing of therapeutic interventions is thus critical, as improper modulation could hinder synaptic refinement or neurogenesis, exacerbating developmental deficits.
Figure 3. Age-dependent microglial functions.
Microglial functions change throughout brain development (see Figure 3). During the embryonic stage, they support neurogenesis via growth factor secretion (e.g., TGF-β). In the postnatal stage, they facilitate synaptic pruning (e.g., complement signaling via C1q). In adolescence, microglia maintain neural homeostasis and synaptic plasticity, while in aging, they shift to mediating inflammatory responses, contributing to neurodegeneration. Adapted from Reference [1].
5. Therapeutic Strategies Targeting Microglia in Pediatric Disorders
Microglia’s role as sensors of CNS pathology makes them ideal targets for therapeutic interventions aimed at reducing neuroinflammation while maintaining their developmental functions [22].
Therapeutic approaches focus on modulating microglial activity through pharmacological and genetic interventions. Minocycline, an anti-inflammatory agent, reduces pro-inflammatory cytokine production and has shown efficacy in preclinical epilepsy models [23]. Gene-editing tools like CRISPR offer the potential to reprogram dysfunctional microglia by targeting inflammatory signaling pathways [6].
Ongoing clinical trials, such as NCT03336297, are evaluating glial-modulating therapies for refractory epilepsy in pediatric populations. These trials emphasize the need to balance microglial suppression with maintaining their critical developmental roles [24]. Furthermore, therapeutic modulation of microglia, such as targeting their pro-inflammatory pathways, has demonstrated efficacy in reducing seizure severity and neuroinflammation in temporal lobe epilepsy [25].
Additionally, microglial replacement therapy, involving transplantation of bone marrow-derived cells or engineered microglia, holds promise for conditions like Rett syndrome. However, challenges such as ensuring integration, maintaining functionality, and avoiding over-suppression of microglia remain significant [17].
Figure 4. Therapeutic approaches for microglial modulation.
Potential therapeutic strategies targeting microglial activity are illustrated (see Figure 4). Pharmacological inhibition, such as reducing inflammatory cytokines; gene editing to modify microglial gene expression; and cell replacement therapies aimed at replenishing functional microglia are highlighted. These interventions are proposed for treating various neurological disorders. Adapted from Reference [26].
6. Future Directions
Future research on microglial dysfunction in pediatric neurological disorders should prioritize identifying reliable biomarkers to distinguish protective versus pathological microglial states. Advanced imaging techniques, such as PET scans with radiolabeled ligands specific to microglial markers, could provide insights into how microglial phenotypes evolve over time [27]. Advanced imaging techniques, such as [11C]PK11195 PET scans, offer a non-invasive means to monitor microglial activation, providing valuable insights into disease progression and therapeutic efficacy, particularly in neurodegenerative disorders [28].
Developing pediatric-specific preclinical models is another crucial avenue for research. Animal models that replicate human developmental stages and incorporate gene-specific manipulations, such as age-specific knockouts of CX3CL1 or IRF8, can elucidate microglial contributions during vulnerable periods [2].
Therapeutic exploration should focus on neurotrophic factors, such as IGF-1 and BDNF, which may counteract microglial dysfunction while addressing challenges like optimizing dosage and safety in pediatric populations [3]. Collaborative studies integrating genetic, epigenetic, and environmental influences on microglial behavior will enhance understanding of early-life risk factors and inform preventive strategies [1].
Finally, translating these findings into precise, age-appropriate interventions requires interdisciplinary collaboration, combining advances in neuroscience, pediatrics, and pharmacology. Addressing these challenges will be essential to mitigate the long-term impacts of microglial dysfunction on neurodevelopment.
7. Conclusion
Microglia play a central role in the developing brain, balancing their roles between promoting neural growth and mediating immune responses. Their involvement in pediatric neurological disorders reflects both their developmental context and the unique features of these conditions. By advancing our understanding of microglial dynamics and their therapeutic modulation, we can develop more targeted and effective treatments for pediatric patients suffering from conditions like ASD, epilepsy, and neurodegenerative diseases.