MHC Class I Function in Neurological Development and Disease

Major Histocompatibility Complex class I (MHC I) molecules, long recognised for their role in antigen presentation to cytotoxic T cells, have emerged as pivotal regulators of neural circuit formation, synaptic remodelling and homeostatic maintenance in both developing and mature brains. During early postnatal life, MHC I expression on neurons and glial cells guides activity-dependent refinement of synapses, contributing to the pruning of excess connections and the consolidation of appropriate pathways. In mature and ageing networks, MHC I continues to influence dendritic spine morphology, synaptic density and the balance between excitation and inhibition. Dysregulation of neuronal MHC I has been implicated in a spectrum of neurological disorders: insufficient MHC I expression may lead to aberrant synaptic retention and impaired plasticity, whereas excessive or ectopic expression can contribute to neuroinflammation and cell loss in conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and autoimmunity. Epigenetic control, intracellular trafficking and activity-dependent signalling converge to fine-tune MHC I levels, ensuring that immune-related signals are co-opted for precise sculpting of the nervous system and, when misregulated, predispose to functional decline and disease.

Research from Nature Portfolio

A foundational study demonstrated that loss of MHC I in aged murine hippocampus leads to pronounced dendritic atrophy, an increase in immature thin spines and a reduction in mature stubby spines, indicating that neuronal MHC I is essential for preserving structural complexity in the ageing brain. Ultrastructural analyses revealed smaller post-synaptic densities and elevated overall synapse density, suggesting compensatory synaptogenesis in the absence of appropriate MHC I signalling. Moreover, aged MHC I-deficient mice exhibited an upregulation of the GluN2B subunit of the NMDA receptor, implicating aberrant glutamatergic function in cognitive decline. This work established a direct link between MHC I expression and maintenance of synaptic architecture during non-pathological ageing, highlighting the molecule’s dual importance in development and longevity of neural circuits.

MHC Class I Function in Neurological Development and Disease publication trend

The graph below shows the total number of articles in mhc class i function in neurological development and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Major Histocompatibility Complex class I (MHC I): A family of cell-surface proteins that present intracellular peptides to immune cells and modulate neuronal connectivity.

β2-microglobulin (B2M): The non-polymorphic light chain component of MHC I, present in blood and cerebrospinal fluid.

Synaptic plasticity: The capacity of synapses to strengthen or weaken over time in response to activity.

Dendritic spine: A small protrusion on a neuron’s dendrite that typically hosts excitatory synapses.

DNA methyltransferase 1 (DNMT1): The enzyme responsible for maintaining DNA methylation patterns and regulating gene expression in post-mitotic cells.

References

1. Role of the Immune System in the Development of the Central Nervous System. Frontiers in Neuroscience (2019).
2. Major Histocompatibility Complex class I proteins are critical for maintaining neuronal structural complexity in the aging brain. Scientific Reports (2016).
3. Plasma β2-microglobulin and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact older adults: the CABLE study. Alzheimer's Research & Therapy (2023).
4. Neuronal MHC Class I Expression Is Regulated by Activity Driven Calcium Signaling. PLOS ONE (2015).
5. DNMT1 regulates expression of MHC class I in post-mitotic neurons. Molecular Brain (2018).