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miR-936 is Increased in Schizophrenia and Inhibits Neural Development and AMPA Receptor-Mediated Synaptic
Debabrata Panja1, You Li1, Michael E Ward2
1Section on Synapse Development and Plasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
Abstract:
MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression and play important roles in the development and function of synapses. miR-936 is a primate-specific miRNA increased in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. The significance of miR-936 increase to schizophrenia is unknown. Here, we show that miR-936 in the human DLPFC is enriched in cortical layer 2/3 and expressed in glutamatergic and GABAergic neurons. miR-936 is increased from layers 2 to 6 of the DLPFC in schizophrenia samples. In neurons derived from human induced pluripotent stem cells (iNs), miR-936 reduces the number of excitatory synapses, inhibits AMPA receptor-mediated synaptic transmission, and increases intrinsic excitability. These effects are mediated by its target gene TMOD2. These results indicate that miR-936 restricts the number of synapses and the strength of glutamatergic synaptic transmission by inhibiting TMOD2 expression. miR-936 upregulation in the DLPFC, therefore, can reduce glutamatergic synapses and weaken excitatory synaptic transmission, which underlie the synaptic pathology and hypofrontality in schizophrenia.
Insights
MicroRNA-936 (miR-936) is elevated in the brain of individuals with schizophrenia. This microRNA reduces excitatory synapses and synaptic transmission by targeting TMOD2, potentially explaining schizophrenia
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression, crucial for neural development and synaptic function.
- miR-936, a primate-specific miRNA, is found at increased levels in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia.
- The functional significance of elevated miR-936 in schizophrenia remains largely unknown.
Purpose of the Study:
- To investigate the role of miR-936 in the human DLPFC.
- To determine the cellular localization and expression patterns of miR-936 in healthy and schizophrenia brains.
- To elucidate the molecular mechanisms by which miR-936 affects synaptic function and neuronal excitability.
Main Methods:
- Analysis of miR-936 enrichment in cortical layers of human DLPFC samples.
- In situ hybridization to determine miR-936 expression in glutamatergic and GABAergic neurons.
- Experiments using human induced pluripotent stem cell-derived neurons (iNs) to assess the impact of miR-936 on synaptic structure, function, and excitability.
- Identification of miR-936 target genes, including TMOD2.
Main Results:
- miR-936 is enriched in cortical layers 2/3 and expressed in both glutamatergic and GABAergic neurons.
- miR-936 levels are elevated across cortical layers 2-6 in the DLPFC of individuals with schizophrenia.
- In iNs, miR-936 significantly reduces excitatory synapse number, impairs AMPA receptor-mediated synaptic transmission, and increases intrinsic neuronal excitability.
- These effects are directly mediated by the inhibition of miR-936's target gene, TMOD2.
Conclusions:
- miR-936 acts as a negative regulator of synapse number and glutamatergic synaptic transmission strength by suppressing TMOD2 expression.
- Upregulation of miR-936 in the DLPFC contributes to reduced glutamatergic synapses and weakened excitatory transmission.
- These miR-936-driven synaptic alterations are implicated in the synaptic pathology and hypofrontality observed in schizophrenia.
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