MiR-936 is Increased in Schizophrenia and Inhibits Neural Development and AMPA Receptor-Mediated Synaptic Transmission

Overview

Journal Schizophr Bull

Publisher Oxford University Press

Specialty Psychiatry

Date 2021 May 3

PMID 33940617

Citations 4

Authors

Debabrata Panja

You Li

Michael E Ward

Zheng Li

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Cox P, Fowler V, Xu B, Sweatt J, Paylor R, Zoghbi H . Mice lacking Tropomodulin-2 show enhanced long-term potentiation, hyperactivity, and deficits in learning and memory. Mol Cell Neurosci. 2003; 23(1):1-12. DOI: 10.1016/s1044-7431(03)00025-3. View

Jung J, Yeom C, Choi Y, Kim S, Lee E, Park M . Simultaneous inhibition of multiple oncogenic miRNAs by a multi-potent microRNA sponge. Oncotarget. 2015; 6(24):20370-87. PMC: 4653011. DOI: 10.18632/oncotarget.4827. View

Fink J, Robinson T, Germain N, Sirois C, Bolduc K, Ward A . Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells. Nat Commun. 2017; 8:15038. PMC: 5413969. DOI: 10.1038/ncomms15038. View

Kriegstein A, Suppes T, Prince D . Cellular and synaptic physiology and epileptogenesis of developing rat neocortical neurons in vitro. Brain Res. 1987; 431(2):161-71. DOI: 10.1016/0165-3806(87)90206-9. View

Dunn K, Kamocka M, McDonald J . A practical guide to evaluating colocalization in biological microscopy. Am J Physiol Cell Physiol. 2011; 300(4):C723-42. PMC: 3074624. DOI: 10.1152/ajpcell.00462.2010. View

Harrison P, Weinberger D . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2004; 10(1):40-68. DOI: 10.1038/sj.mp.4001558. View

Gee D, Humphreys K, Flannery J, Goff B, Telzer E, Shapiro M . A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry. J Neurosci. 2013; 33(10):4584-93. PMC: 3670947. DOI: 10.1523/JNEUROSCI.3446-12.2013. View

Ebert M, Neilson J, Sharp P . MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007; 4(9):721-6. PMC: 3857099. DOI: 10.1038/nmeth1079. View

Narayanan R, Udvary D, Oberlaender M . Cell Type-Specific Structural Organization of the Six Layers in Rat Barrel Cortex. Front Neuroanat. 2017; 11:91. PMC: 5645532. DOI: 10.3389/fnana.2017.00091. View

10.

Lesh T, Niendam T, Minzenberg M, Carter C . Cognitive control deficits in schizophrenia: mechanisms and meaning. Neuropsychopharmacology. 2010; 36(1):316-38. PMC: 3052853. DOI: 10.1038/npp.2010.156. View

11.

Schmidt-Hieber C, Jonas P, Bischofberger J . Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature. 2004; 429(6988):184-7. DOI: 10.1038/nature02553. View

12.

Torres-Torrelo J, Torres B, Carrascal L . Modulation of the input-output function by GABAA receptor-mediated currents in rat oculomotor nucleus motoneurons. J Physiol. 2014; 592(22):5047-64. PMC: 4259542. DOI: 10.1113/jphysiol.2014.276576. View

13.

Raghavachari S, Lisman J . Properties of quantal transmission at CA1 synapses. J Neurophysiol. 2004; 92(4):2456-67. DOI: 10.1152/jn.00258.2004. View

14.

Beveridge N, Cairns M . MicroRNA dysregulation in schizophrenia. Neurobiol Dis. 2011; 46(2):263-71. DOI: 10.1016/j.nbd.2011.12.029. View

15.

Ma L, Reinhardt F, Pan E, Soutschek J, Bhat B, Marcusson E . Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nat Biotechnol. 2010; 28(4):341-7. PMC: 2852471. DOI: 10.1038/nbt.1618. View

16.

Kolluri N, Sun Z, Sampson A, Lewis D . Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am J Psychiatry. 2005; 162(6):1200-2. DOI: 10.1176/appi.ajp.162.6.1200. View

17.

Hensch T . Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005; 6(11):877-88. DOI: 10.1038/nrn1787. View

18.

Vigneault E, Poirel O, Riad M, Prudhomme J, Dumas S, Turecki G . Distribution of vesicular glutamate transporters in the human brain. Front Neuroanat. 2015; 9:23. PMC: 4350397. DOI: 10.3389/fnana.2015.00023. View

19.

Rosa F, Dhingra A, Uysal B, Mendis G, Loeffler H, Elsen G . In Vitro Differentiated Human Stem Cell-Derived Neurons Reproduce Synaptic Synchronicity Arising during Neurodevelopment. Stem Cell Reports. 2020; 15(1):22-37. PMC: 7363884. DOI: 10.1016/j.stemcr.2020.05.015. View

20.

Gogtay N, Giedd J, Lusk L, Hayashi K, Greenstein D, Vaituzis A . Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci U S A. 2004; 101(21):8174-9. PMC: 419576. DOI: 10.1073/pnas.0402680101. View