Abstract
Dlx homeodomain transcription factors are essential during embryonic development for the production of forebrain GABAergic interneurons. Here we show that Dlx1 is also required for regulating the functional longevity of cortical and hippocampal interneurons in the adult brain. We demonstrate preferential Dlx1 expression in a subset of cortical and hippocampal interneurons which, in postnatal Dlx1 mutants, show a time-dependent reduction in number. This reduction preferentially affects calretinin+ (bipolar cells) and somatostatin+ subtypes (for example, bitufted cells), whereas parvalbumin+ subpopulations (basket cells and chandelier cells) seem to be unaffected. Cell transplantation analysis demonstrates that interneuron loss reflects cell-autonomous functions of Dlx1. The decrease in the number of interneurons was associated with a reduction of GABA-mediated inhibitory postsynaptic current in neocortex and hippocampus in vitro and cortical dysrhythmia in vivo. Dlx1 mutant mice show generalized electrographic seizures and histological evidence of seizure-induced reorganization, linking the Dlx1 mutation to delayed-onset epilepsy associated with interneuron loss.
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Acknowledgements
We thank R. Nicoll for physiological advice. I.C. thanks J. Palop and U. Borello for helpful discussions, M. Alvarez-Dolado for advice in cell transplantations, and the L. Mucke laboratory (Gladstone Institute of Neurological Disease, UCSF) for sharing the BioQuant Image Analysis. This work was supported by funds to J.L.R.R. (Nina Ireland, National Institute of Mental Health RO1 MH49428 and K05 MH065670), I.C. (National Alliance for Research on Schizophrenia and Depression Young Investigator Award), S.C.B. (US National Institutes of Health RO1 NS40272 and Citizens United for Research in Epilepsy) and J.L.N. (National Institute of Neurological Disorders and Stroke NS 29709 and National Institute of Child Health and Human Development HD24064, Baylor Mental Retardation and Developmental Disabilities Research Center).
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Supplementary information
Supplementary Fig. 1
Normal numbers and layer distribution of Gad67+ neurons in postnatal Dlx1−/− mice. (PDF 4548 kb)
Supplementary Fig. 2
Normal numbers of PV+ interneurons in Dlx1−/− mice. (PDF 6893 kb)
Supplementary Fig. 3
Subtype-specific reduction of GABAergic neurons in Dlx1−/− mice. (PDF 7879 kb)
Supplementary Fig. 4
Preserved expression levels of interneuron markers in Dlx1−/− Dlx2−/− mice. (PDF 5743 kb)
Supplementary Fig. 5
Increased numbers of TUNEL+ profiles in neocortex and hippocampus of Dlx1−/− mice. (PDF 7061 kb)
Supplementary Fig. 6
Reduced GABAergic synaptic transmission in neocortex and hippocampus of Dlx1−/− mice. (PDF 1693 kb)
Supplementary Fig. 7
Distribution of amplitude and decay time constant of mIPSCs in Dlx1−/− mice. (PDF 2049 kb)
Supplementary Fig. 8
Expression of Dlx2 and Dlx5 in cortical interneurons. (PDF 6310 kb)
Supplementary Table 1
Decay time constant and rise time values of spontaneous and miniature IPSCs in neocortex and CA3 pyramidal cells from Dlx1+/+ and Dlx1−/− mice. (PDF 91 kb)
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Cobos, I., Calcagnotto, M., Vilaythong, A. et al. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat Neurosci 8, 1059–1068 (2005). https://doi.org/10.1038/nn1499
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DOI: https://doi.org/10.1038/nn1499
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