Schizophrenia is a mental disorder that affects how people think, feel, and behave.
It involves problems with hallucinations, delusions, disorganized thinking, lack of motivation, and impaired functioning.
Schizophrenia affects about 1% of the population and typically starts in late adolescence or early adulthood. The causes are still poorly understood.
In a new study, researchers found important clues to how schizophrenia arises by studying mice with mutations in a gene called Grin2a.
Key Facts:
- Grin2a codes for part of a receptor in brain cells that responds to the chemical messenger glutamate.
- Mutations in Grin2a increase the risk of schizophrenia in humans.
- Studying mice with reduced Grin2a gave insights into schizophrenia at multiple levels, from molecules to behavior.
- The mouse data support two major theories about schizophrenia causes – excess dopamine activity and reduced NMDA receptor function.
- Unexpected roles were found for non-neuron brain cells called glia and effects on metabolism.
- The findings open new avenues for understanding and treating schizophrenia.
Source: Neuron 2023 Aug 23
The Grin2a Gene and Its Protein Product
Genes are stretches of DNA that contain instructions for making proteins.
Proteins are molecules that perform important functions in our cells.
Grin2a is the name of a gene that codes for a protein called GluN2A. GluN2A is a subunit, or component, of NMDA receptors.
NMDA receptors are proteins on brain cells that respond to the neurotransmitter glutamate. Glutamate is a chemical messenger that brain cells use to communicate with each other.
NMDA receptors play crucial roles in brain functions like learning, memory, and cognition.
They are made of different subunits – GluN2A is one of them.
The different subunits put together form a functioning NMDA receptor.
How Mutations in Grin2a Are Linked to Schizophrenia
In humans, mutations that impair the function of the Grin2a gene increase the risk of developing schizophrenia.
These mutations are quite rare and are thought to reduce the activity of GluN2A and NMDA receptors.
Some key questions arise – how does having defective Grin2a lead to schizophrenia? Which brain regions and cell types are affected?
What specific brain functions go awry? Answering such questions is hard in human patients but studying mice with mutated Grin2a provides opportunities to get molecular and functional insights.
Creating Mice with Defective Grin2a to Study Schizophrenia
To mimic the Grin2a mutations in humans, researchers genetically engineered mice to have reduced levels of normal Grin2a.
They studied mice missing one copy of Grin2a (called heterozygous) and mice missing both copies (called homozygous mutants).
The effects of defective Grin2a were analyzed in these mice at different ages and in several brain regions implicated in schizophrenia, including the prefrontal cortex, hippocampus, and striatum.
Numerous experiments were done to compare the mutant mice to normal mice.
Advanced techniques measured brain cell gene activity, protein levels, electrical signaling, and behavior.
This multi-pronged approach provided a detailed picture of how reduced Grin2a affects various molecular, cellular, and nervous system processes relevant to schizophrenia.
Widespread Effects of Grin2a Mutations Across Brain Regions and Cell Types
The study found that even removing just one copy of Grin2a had big effects on gene activity in mice.
Surprisingly, the effects were nearly as strong as removing both copies.
Hundreds of genes were affected in brain regions like the prefrontal cortex and hippocampus.
Different types of brain cells were altered, including two main classes of neurons – excitatory and inhibitory neurons.
Excitatory neurons activate other neurons while inhibitory neurons calm them down.
Non-neuronal cells called glia were also affected. Glia support and protect neurons.
The gene expression changes in Grin2a mutant mice were generally greater at 12 weeks of age than at 4 weeks.
This could relate to schizophrenia emerging in late adolescence/early adulthood.
Opposite Effects in Prefrontal Cortex Versus Hippocampus
Intriguingly, the prefrontal cortex and hippocampus were affected in opposite ways by the Grin2a mutations.
The prefrontal cortex showed reduced activity in the mutants, whereas the hippocampus became overactive.
This matches patterns seen in schizophrenia patients – too little prefrontal activity but excess hippocampal activity.
The reduced prefrontal activity is thought to impair cognitive functions like working memory and decision-making in schizophrenia.
The excess hippocampal activity may contribute to psychosis.
Dopamine and Glutamate – Major Clues to Schizophrenia
Two neurotransmitters heavily implicated in schizophrenia are dopamine and glutamate.
The study found that mice with defective Grin2a had altered dopamine signaling in brain regions like the striatum.
Many genes regulated by dopamine were increased in the striatum of mutant mice.
Mice also became more hyperactive when given amphetamine, which stimulates dopamine release.
Excess dopamine activity is thought to play a role in the psychotic symptoms of schizophrenia.
These data provide new evidence linking Grin2a mutations to dopamine abnormalities in schizophrenia.
Since Grin2a codes for part of the NMDA glutamate receptor, the results also reinforce altered glutamate signaling in schizophrenia.
NMDA receptors interact with dopamine pathways in complex ways.
The study supports the idea that NMDA receptor problems can lead to secondary excessive dopamine activity.
Targeting the dopamine abnormalities alone does not treat all schizophrenia symptoms.
Unexpected Roles for Non-Neuronal Cells
Glial cells, which support neurons, showed interesting gene activity changes in the mutant mice.
For example, a process related to cholesterol production was altered in astrocytes – star-shaped glial cells.
Cholesterol is an essential component of cell membranes and myelin insulation on nerve fibers.
The significance of this cholesterol pathway change needs more research.
Another intriguing finding was the mislocalization of proteins involved in RNA splicing and processing from the nucleus to the cytoplasm in brain cells of mutant mice.
Dysfunctional RNA processing has been linked to other neurological disorders.
These data suggest non-neuronal cells and basic biological processes like metabolism contribute to schizophrenia in currently unknown ways.
Future studies should explore these possibilities.
Matching Gene Mutations in Mice to Human Disease
This study highlights the power of engineering mice with mutations in high-risk schizophrenia genes identified from human genetic studies.
GRIN2A emerged as a prime schizophrenia risk gene from analyzing the DNA of thousands of patients.
While human brains are far more complex, mice allow direct experiments to test the effects of gene mutations relevant to human patients.
This enables a mechanistic understanding not possible from limited patient studies.
Mice with Grin2a mutations displayed numerous schizophrenia-related changes at molecular, cellular, chemical signaling, and behavioral levels.
The findings strengthen the case that defective GRIN2A is an important causal factor in schizophrenia and provide leads for better treatments.
Studying other top schizophrenia risk genes mutated in mice will likely yield further insights.
Ultimately, understanding how combinations of genetic and environmental factors converge upon common biological pathways may solve the mystery of schizophrenia.
References
- Study: Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice
- Authors: Zohreh Farsi et al. (2023)
