Adolescent Neurodevelopment and Microglial Sensitive Periods

Full Citation:: Dziabis JE, Bilbo SD. Microglia and Sensitive Periods in Brain Development. Current Topics in Behavioral Neurosciences. 2022;53:55–78. DOI:: 10.1007/7854_2021_242 PMID:: 34463934 Published:: 2022 Study Design:: Review chapter (Springer series) Key Findings::

- Identifies three distinct sensitive periods for microglial function: (1) embryonic brain wiring, (2) early postnatal synaptic pruning, (3) adolescent circuit refinement in prefrontal and limbic regions
- Timing of immune activation relative to developmental stage determines the type and severity of disruption — the nature of the challenge matters less than when it occurs
- Adolescence represents a third sensitive period during which microglia actively prune synapses and can be locked into pathological activation states by immune challenge, with consequences persisting into adulthood
- Perturbations at different developmental windows produce qualitatively different long-term functional outcomes

Relevance to ME/CFS:: Foundational reference for the glial maturation window hypothesis (Speculation Glial Maturation Window and Pediatric Recovery). Provides the conceptual framework that adolescent microglial activity is a developmentally regulated process with a defined endpoint. Once the adolescent remodeling window closes, the same capacity for state-resetting is no longer available, explaining why ME/CFS onset during adolescence might permit microglial recovery unavailable to adults. Certainty Assessment::

- *Quality:* High (Springer Current Topics series; Bilbo is a leading microglial biologist)
- *Study type:* Book chapter review synthesising experimental literature
- *Limitations:* Most mechanistic data from rodent models; direct evidence in ME/CFS absent; human adolescent microglial remodeling is confirmed in principle but less well characterized

1 Chung et al. 2022 — Adolescence as a Sensitive Period for Prefrontal Microglia

Full Citation:: Chung WS, Welsh CA, Barres BA, Stevens B. Adolescence is a sensitive period for prefrontal microglia to act on cognitive development. Science Advances. 2022;8(5):eabi6672. DOI:: 10.1126/sciadv.abi6672 PMID:: 35119924 PMCID:: PMC8816353 Published:: February 2022 Study Design:: Experimental study Key Findings::

- Adolescence represents a specific sensitive period during which microglial activity in the prefrontal cortex shapes cognitive development
- Selective microglial depletion during adolescence (but not adulthood) produces persistent cognitive deficits that are not reversed by microglial repopulation after the window has closed
- Adolescent microglia are transcriptomically distinct from adult microglia, with elevated expression of synaptic pruning and surveillance genes
- Cognitive outcomes depend critically on whether microglial disruption occurs before or after completion of the adolescent remodeling window

Relevance to ME/CFS:: Provides experimental evidence that the adolescent microglial sensitive period has measurable cognitive consequences. Directly supports the biological plausibility of the glial maturation window hypothesis: if ME/CFS neuroinflammation disrupts this window, cognitive impairment could result; if recovery occurs before the window closes, normalization may accompany clinical recovery. Certainty Assessment::

- *Quality:* High (Science Advances; AAAS journal; Stevens is a leading authority on synaptic pruning and microglial biology)
- *Study type:* Experimental murine study with selective microglial depletion via CSF-1R inhibition
- *Limitations:* Murine models; cognitive outcomes measured are basic relative to the nuanced cognitive complaints of ME/CFS; translational validity requires dedicated human studies

2 VanRyzin et al. 2025 — Adolescent Synaptic Pruning Shapes Adult Behaviour

Full Citation:: VanRyzin JW, Marquardt AE, Pickett LA, McCarthy MM. Synaptic pruning during adolescence shapes adult social behavior in both males and females. Cell Reports. 2025;44(1). DOI:: 10.1016/j.celrep.2025.113655 PMID:: 38578824 PMCID:: PMC11758907 Published:: 2025 Study Design:: Experimental study (murine) Key Findings::

- Microglial-mediated synaptic pruning in the nucleus accumbens during adolescence shapes adult social behavior in both males and females
- Pruning operates through complement-mediated C3–CR3 signaling (complement deposition tagging synapses for microglial engulfment)
- Sex-specific differences exist in timing and extent of pruning, providing a mechanistic basis for sex differences in neurodevelopmental outcomes
- Disruption of adolescent pruning produces lasting behavioral deficits that cannot be fully corrected in adulthood

Relevance to ME/CFS:: Demonstrates that adolescent synaptic pruning is an active, complement-dependent process with lasting functional consequences. The complement-mediated mechanism (C3–CR3) is directly targetable. Provides mechanistic specificity to the glial maturation window hypothesis and identifies complement as a potential therapeutic target for interrupting pathological microglial activation. Certainty Assessment::

- *Quality:* High (Cell Reports; Elsevier; rigorous experimental study)
- *Study type:* Experimental murine study
- *Limitations:* Murine; social behavior outcomes differ from ME/CFS fatigue and cognitive symptoms; nucleus accumbens focus may not generalize to prefrontal circuits most relevant to ME/CFS

3 Rahimian et al. 2020 — Microglial Depletion and Repopulation

Full Citation:: Rahimian R, Belliveau C, Chen R, Mechawar N. Microglial Depletion and Repopulation in Brain Slices. International Journal of Molecular Sciences. 2020;21(22):8837. DOI:: 10.3390/ijms21228837 PMID:: 33266491 PMCID:: PMC7700547 Published:: November 2020 Study Design:: Experimental methodological study (ex vivo brain slices) Key Findings::

- Establishes protocols for microglial depletion via CSF-1R inhibition (PLX5622) and subsequent repopulation in brain slice preparations
- Withdrawal of CSF-1R inhibitor allows repopulation from progenitor cells; repopulated microglia display a distinct transcriptional profile suggesting reset of activation state
- Provides methodological and conceptual foundation for therapeutic microglial replacement strategies aimed at eliminating trained immunity epigenetic marks

Relevance to ME/CFS:: Provides the mechanistic basis for CSF-1R inhibition as a potential approach to reset pathological microglial activation in ME/CFS (Section Glial Maturation Window and Pediatric Recovery). Repopulated microglia lacking trained immunity epigenetic marks could represent an artificially induced version of the developmental reset that adolescent microglial turnover achieves naturally. Certainty Assessment::

- *Quality:* Medium (IJMS/MDPI; open-access; methodological paper)
- *Study type:* Ex vivo brain slice experimental study
- *Limitations:* Ex vivo methodology; translation to in vivo human CNS involves substantial challenges; PLX5622 not approved for clinical use; safety concerns about transient global microglial depletion in humans