NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2021 Oct 11

PMID 34630033

Citations 8

Authors

Vivek Mahadevan

Apratim Mitra

Yajun Zhang

Xiaoqing Yuan

Areg Peltekian

Ramesh Chittajallu

Caroline Esnault

Dragan Maric

Christopher Rhodes

Kenneth A Pelkey

Ryan Dale

Timothy J Petros

Chris J McBain

Affiliations

Soon will be listed here.

Abstract

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical, and physiological properties. However, the molecular mechanisms regulating their maturation remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene mediates transcriptional regulation of gene expression in specific subtypes of MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific early developmental Grin1 loss results in a broad downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs in the juvenile brain. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

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References

Nikouei K, Munoz-Manchado A, Hjerling-Leffler J . BCL11B/CTIP2 is highly expressed in GABAergic interneurons of the mouse somatosensory cortex. J Chem Neuroanat. 2015; 71:1-5. DOI: 10.1016/j.jchemneu.2015.12.004. View

Priya R, Paredes M, Karayannis T, Yusuf N, Liu X, Jaglin X . Activity Regulates Cell Death within Cortical Interneurons through a Calcineurin-Dependent Mechanism. Cell Rep. 2018; 22(7):1695-1709. PMC: 6215776. DOI: 10.1016/j.celrep.2018.01.007. View

Butler A, Hoffman P, Smibert P, Papalexi E, Satija R . Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36(5):411-420. PMC: 6700744. DOI: 10.1038/nbt.4096. View

He M, Tucciarone J, Lee S, Nigro M, Kim Y, Levine J . Strategies and Tools for Combinatorial Targeting of GABAergic Neurons in Mouse Cerebral Cortex. Neuron. 2016; 91(6):1228-1243. PMC: 5223593. DOI: 10.1016/j.neuron.2016.08.021. View

Valero M, Viney T, Machold R, Mederos S, Zutshi I, Schuman B . Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex. Nat Neurosci. 2021; 24(3):401-411. PMC: 9662703. DOI: 10.1038/s41593-021-00797-6. View

Smoot M, Ono K, Ruscheinski J, Wang P, Ideker T . Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2010; 27(3):431-2. PMC: 3031041. DOI: 10.1093/bioinformatics/btq675. View

Butt S, Sousa V, Fuccillo M, Hjerling-Leffler J, Miyoshi G, Kimura S . The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron. 2008; 59(5):722-32. PMC: 2562525. DOI: 10.1016/j.neuron.2008.07.031. View

Manent J, Jorquera I, Ben-Ari Y, Aniksztejn L, Represa A . Glutamate acting on AMPA but not NMDA receptors modulates the migration of hippocampal interneurons. J Neurosci. 2006; 26(22):5901-9. PMC: 6675217. DOI: 10.1523/JNEUROSCI.1033-06.2006. View

Homayoun H, Moghaddam B . NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007; 27(43):11496-500. PMC: 2954603. DOI: 10.1523/JNEUROSCI.2213-07.2007. View

10.

Matta J, Pelkey K, Craig M, Chittajallu R, Jeffries B, McBain C . Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity. Nat Neurosci. 2013; 16(8):1032-41. PMC: 4132661. DOI: 10.1038/nn.3459. View

11.

Bortone D, Polleux F . KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner. Neuron. 2009; 62(1):53-71. PMC: 3314167. DOI: 10.1016/j.neuron.2009.01.034. View

12.

Zimmer G, Garcez P, Rudolph J, Niehage R, Weth F, Lent R . Ephrin-A5 acts as a repulsive cue for migrating cortical interneurons. Eur J Neurosci. 2008; 28(1):62-73. DOI: 10.1111/j.1460-9568.2008.06320.x. View

13.

Komuro H, Rakic P . Selective role of N-type calcium channels in neuronal migration. Science. 1992; 257(5071):806-9. DOI: 10.1126/science.1323145. View

14.

Wamsley B, Jaglin X, Favuzzi E, Quattrocolo G, Nigro M, Yusuf N . Rbfox1 Mediates Cell-type-Specific Splicing in Cortical Interneurons. Neuron. 2018; 100(4):846-859.e7. PMC: 6541232. DOI: 10.1016/j.neuron.2018.09.026. View

15.

Fishell G, Kepecs A . Interneuron Types as Attractors and Controllers. Annu Rev Neurosci. 2019; 43:1-30. PMC: 7064158. DOI: 10.1146/annurev-neuro-070918-050421. View

16.

Xu Q, Tam M, Anderson S . Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J Comp Neurol. 2007; 506(1):16-29. DOI: 10.1002/cne.21529. View

17.

Wamsley B, Fishell G . Genetic and activity-dependent mechanisms underlying interneuron diversity. Nat Rev Neurosci. 2017; 18(5):299-309. DOI: 10.1038/nrn.2017.30. View

18.

Munoz-Manchado A, Bengtsson Gonzales C, Zeisel A, Munguba H, Bekkouche B, Skene N . Diversity of Interneurons in the Dorsal Striatum Revealed by Single-Cell RNA Sequencing and PatchSeq. Cell Rep. 2018; 24(8):2179-2190.e7. PMC: 6117871. DOI: 10.1016/j.celrep.2018.07.053. View

19.

Marin O, YARON A, Bagri A, Tessier-Lavigne M, Rubenstein J . Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science. 2001; 293(5531):872-5. DOI: 10.1126/science.1061891. View

20.

Carlen M, Meletis K, Siegle J, Cardin J, Futai K, Vierling-Claassen D . A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol Psychiatry. 2011; 17(5):537-48. PMC: 3335079. DOI: 10.1038/mp.2011.31. View