Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability

Area of Science:

• Neuroscience
• Metabolic pathways
• Genetic disorders

Background:

• Astrocytes provide crucial metabolic support to neurons via aerobic glycolysis.
• The role of astrocytic metabolic dysfunction in intellectual disability (ID) is not fully understood.
• SNX27 mutations are linked to ID, but their impact on astrocyte metabolism is unclear.

Purpose of the Study:

• To investigate the causal role of an ID-associated SNX27 mutation (R198W) in cognitive deficits.
• To elucidate the mechanisms by which SNX27 mutations affect astrocytic metabolism and neuronal function.
• To explore potential therapeutic strategies for ID by targeting astrocytic metabolism.

Main Methods:

• Generated SNX27 R196W knock-in mouse models.
• Assessed synaptic function and learning behaviors in mutant mice.
• Analyzed astrocytic glucose uptake (GLUT1), lactate production, and astrocyte reactivity.
• Administered lactate supplementation and ketogenic diet to evaluate cognitive recovery.

Main Results:

• SNX27 R196W mice exhibited impaired synaptic function and learning deficits.
• The mutation attenuated astrocytic glucose uptake and lactate production, shifting astrocytes to a reactive state.
• Lactate supplementation or ketogenic diet normalized neuronal oxidative phosphorylation and reversed cognitive impairments.
• Astrocytic SNX27 is critical for maintaining glucose supply and glycolysis.

Conclusions:

• Astrocytic SNX27 plays a vital role in neuronal support through glucose metabolism.
• Altered astrocytic metabolism due to SNX27 mutations disrupts astrocyte-neuron interactions, contributing to ID.
• Restoring astrocytic metabolic function presents a potential therapeutic avenue for intellectual disability.