Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis

Ramon Pla; Amelia Stanco; Mackenzie A. Howard; Anna N. Rubin; Daniel Vogt; Niall Mortimer; Inma Cobos; Gregory Brian Potter; Susan Lindtner; James D. Price; Alex S. Nord; Axel Visel; Christoph E. Schreiner; Scott C. Baraban; David H. Rowitch; John L.R. Rubenstein

doi:10.1093/cercor/bhx241

Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis

Ramon Pla, Amelia Stanco, Mackenzie A. Howard, Anna N. Rubin, Daniel Vogt, Niall Mortimer, Inma Cobos, Gregory Brian Potter, Susan Lindtner, James D. Price, Alex S. Nord, Axel Visel, Christoph E. Schreiner, Scott C. Baraban, David H. Rowitch, John L.R. Rubenstein

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV + CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.

Original language	English (US)
Pages (from-to)	3797-3815
Number of pages	19
Journal	Cerebral Cortex
Volume	28
Issue number	11
DOIs	https://doi.org/10.1093/cercor/bhx241
State	Published - Nov 1 2018

Keywords

Dlx
Gad
cortex
interneuron
synapse

ASJC Scopus subject areas

Cognitive Neuroscience
Cellular and Molecular Neuroscience

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10.1093/cercor/bhx241

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Pla, R., Stanco, A., Howard, M. A., Rubin, A. N., Vogt, D., Mortimer, N., Cobos, I., Potter, G. B., Lindtner, S., Price, J. D., Nord, A. S., Visel, A., Schreiner, C. E., Baraban, S. C., Rowitch, D. H., & Rubenstein, J. L. R. (2018). Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis. Cerebral Cortex, 28(11), 3797-3815. https://doi.org/10.1093/cercor/bhx241

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abstract = "The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV + CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.",

keywords = "Dlx, Gad, cortex, interneuron, synapse",

author = "Ramon Pla and Amelia Stanco and Howard, {Mackenzie A.} and Rubin, {Anna N.} and Daniel Vogt and Niall Mortimer and Inma Cobos and Potter, {Gregory Brian} and Susan Lindtner and Price, {James D.} and Nord, {Alex S.} and Axel Visel and Schreiner, {Christoph E.} and Baraban, {Scott C.} and Rowitch, {David H.} and Rubenstein, {John L.R.}",

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T1 - Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis

AU - Pla, Ramon

AU - Stanco, Amelia

AU - Howard, Mackenzie A.

AU - Rubin, Anna N.

AU - Vogt, Daniel

AU - Mortimer, Niall

AU - Cobos, Inma

AU - Potter, Gregory Brian

AU - Lindtner, Susan

AU - Price, James D.

AU - Nord, Alex S.

AU - Visel, Axel

AU - Schreiner, Christoph E.

AU - Baraban, Scott C.

AU - Rowitch, David H.

AU - Rubenstein, John L.R.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV + CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.

AB - The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV + CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.

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Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis

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