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The Role of Microglia in Synaptic Pruning and Neurodevelopmental Disorders

By Alissa Sofia Maria Bocance


Abstract

The central nervous system's (CNS) resident immune cells, known as microglia, are vital to synaptic pruning, a process necessary for healthy neurodevelopment. Numerous neurodevelopmental illnesses, such as attention deficit hyperactivity disorder (ADHD), schizophrenia, and autism spectrum disorder (ASD), have been linked to dysregulation of synaptic pruning. This study investigates the molecular pathways and mechanisms through which microglia drive synaptic pruning, as well as how abnormalities in these processes lead to neurodevelopmental problems. Gaining insight into microglial dysfunction could lead to novel therapeutic approaches for neurodevelopmental disorders. 


Introduction

To guarantee effective neural communication, synapse generation, removal, and refinement are all part of the intricately coordinated process of neurodevelopment. Through synaptic pruning, which mostly takes place in the early stages of postnatal development, microglia have become important actors in reshaping brain networks. Although cognitive and sensory function depend on normal synaptic pruning, neurological diseases have been associated with both excessive and insufficient pruning. The implications of microglial-mediated synaptic pruning in neurodevelopmental disorders are covered in this review. 


Microglial-Mediated Synaptic Pruning

The developing brain is shaped by microglia, which recognize and absorb weak or superfluous connections. This procedure entails: 

  • Complement System Activation: Synapses are marked for elimination by microglia, via CR3 receptors, by the classical complement cascade, specifically C1q and C3.

  • TAM Receptors: The Tyro3, Axl, and MerTK (TAM) family of receptor tyrosine kinases regulates phagocytosis of synapses.

  • Fractalkine Signaling: Neurons express fractalkine (CX3CL1), which binds to CX3CR1 receptors on microglia, modulating synaptic pruning.

  • TGF-β and Interleukin Signaling: These cytokines influence microglial activation and synapse remodeling.


Microglial Dysfunction in Neurodevelopmental Disorders

Autism Spectrum Disorder (ASD)

Excessive synaptic density caused by poor microglial pruning has been linked to ASD, according to studies. Aberrant synapse removal is caused by mutations in genes that control microglial activity, such as TSC1/2 and PTEN. Microglia's overactive mTOR signaling also aids in synaptic retention, which may be the cause of the sensory overload and social behavior problems seen in ASD. 

Schizophrenia

On the other hand, excessive synaptic pruning has been connected to schizophrenia. Reduced dendritic spine density has been found in postmortem examinations, and excessive pruning has been linked to the complement system's C4A variation by genome-wide association studies (GWAS). Adolescence is a critical period for synaptic reorganization, and microglial activation during this time may be a factor in cognitive impairments and psychotic symptoms. 

ADHD and Other Disorders

Recent data points to altered microglial function in ADHD, which may upset the equilibrium between synaptic retention and clearance. Hyperactivity and attentional problems may be caused by cytokine signaling changes and hyperactivation of inflammatory pathways. 


Therapeutic Implications

One promising approach to treating neurodevelopmental problems is to target microglial dysfunction. Among the possible tactics are: 

  • Complement Inhibitors: Blocking C1q or C3, to reduce excessive synaptic pruning in schizophrenia.

  • mTOR Modulators: Regulating mTOR signaling to enhance synaptic elimination in ASD.

  • Anti-Inflammatory Therapies: Modulating microglial activity using minocycline or other immunomodulatory agents.


Conclusion

Normal brain development depends on microglia-mediated synaptic pruning, and neurodevelopmental disorders are largely caused by its dysregulation. Novel treatments for disorders like ASD, schizophrenia, and ADHD may result from an understanding of the molecular processes underpinning microglial activity. In order to reestablish synaptic homeostasis, future research should concentrate on improving therapeutic approaches.



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