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A concerted neuron-astrocyte program declines in ageing and schizophrenia
Emi Ling1,2, James Nemesh3,4, Melissa Goldman3,4
1Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. eling@broadinstitute.org.
Nature
|March 6, 2024
Summary
A newly identified synaptic neuron and astrocyte program (SNAP) links brain cell communication to individual differences. This program
Area of Science:
- Neuroscience
- Cellular Biology
- Genetics
Background:
- Human brain variation is not understood at the cellular level.
- Cortical astrocytes and neurons play crucial roles in brain function.
- Schizophrenia and aging impact cognitive flexibility and plasticity.
Purpose of the Study:
- To investigate the relationship between cortical neurons and astrocytes in the human brain.
- To identify cellular mechanisms underlying interindividual differences and neurodevelopmental/neurodegenerative conditions.
- To explore the role of the synaptic neuron and astrocyte program (SNAP) in health and disease.
Main Methods:
- Single-nucleus RNA sequencing of prefrontal cortex from 191 human donors (ages 22-97).
- Analysis included healthy individuals and those with schizophrenia.
- Latent-factor analysis to identify gene expression relationships.
Main Results:
- A positive correlation was found between neuronal synaptic gene expression and astrocyte synaptic/cholesterol synthesis gene expression, termed the synaptic neuron and astrocyte program (SNAP).
- Reduced SNAP expression was observed in astrocytes, glutamatergic neurons, and GABAergic neurons in individuals with schizophrenia and in older adults.
- Genes within SNAP are enriched for genetic risk factors associated with schizophrenia.
Conclusions:
- SNAP represents a key cellular mechanism underlying normal human interindividual brain variation.
- Dysregulation of SNAP may be a convergent point for pathophysiology in conditions like schizophrenia and aging.
- SNAP offers a cellular framework for understanding cognitive decline and brain plasticity.
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