Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy

被引:395
作者
Cobos, I [1 ]
Calcagnotto, ME
Vilaythong, AJ
Thwin, MT
Noebels, JL
Baraban, SC
Rubenstein, JLR
机构
[1] Univ Calif San Francisco, Dept Psychiat, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94158 USA
[2] Univ Calif San Francisco, Dept Neurol Surg, Epilepsy Res Lab, San Francisco, CA 94143 USA
[3] Baylor Coll Med, Dept Neurol, Dev Neurogenet Lab, Houston, TX 77030 USA
关键词
D O I
10.1038/nn1499
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1059 / 1068
页数:10
相关论文
共 49 条
[11]   Interneuron diversity series: Rhythm and mood in perisomatic inhibition [J].
Freund, TF .
TRENDS IN NEUROSCIENCES, 2003, 26 (09) :489-495
[12]   Three distinct families of GABAergic neurons in rat visual cortex [J].
Gonchar, Y ;
Burkhalter, A .
CEREBRAL CORTEX, 1997, 7 (04) :347-358
[13]   Axo-axonic Synapses formed by somatostatin-expressing GABAergic neurons in rat and monkey visual cortex [J].
Gonchar, Y ;
Turney, S ;
Price, JL ;
Burkhalter, A .
JOURNAL OF COMPARATIVE NEUROLOGY, 2002, 443 (01) :1-14
[14]   Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex [J].
Gupta, A ;
Wang, Y ;
Markram, H .
SCIENCE, 2000, 287 (5451) :273-278
[15]   Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome [J].
Horike, S ;
Cai, ST ;
Miyano, M ;
Cheng, JF ;
Kohwi-Shigematsu, T .
NATURE GENETICS, 2005, 37 (01) :31-40
[16]   VARIETIES AND DISTRIBUTION OF NON-PYRAMIDAL CELLS IN SOMATIC SENSORY CORTEX OF SQUIRREL-MONKEY [J].
JONES, EG .
JOURNAL OF COMPARATIVE NEUROLOGY, 1975, 160 (02) :205-+
[17]   GABAergic cell subtypes and their synaptic connections in rat frontal cortex [J].
Kawaguchi, Y ;
Kubota, Y .
CEREBRAL CORTEX, 1997, 7 (06) :476-486
[18]   Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans [J].
Kitamura, K ;
Yanazawa, M ;
Sugiyama, N ;
Miura, H ;
Iizuka-Kogo, A ;
Kusaka, M ;
Omichi, K ;
Suzuki, R ;
Kato-Fukui, Y ;
Kamiirisa, K ;
Matsuo, M ;
Kamijo, S ;
Kasahara, M ;
Yoshioka, H ;
Ogata, T ;
Fukuda, T ;
Kondo, I ;
Kato, M ;
Dobyns, WB ;
Yokoyama, M ;
Morohashi, K .
NATURE GENETICS, 2002, 32 (03) :359-369
[19]   Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo [J].
Klausberger, T ;
Magill, PJ ;
Márton, LF ;
Roberts, JDB ;
Cobden, PM ;
Buzsáki, G ;
Somogyi, P .
NATURE, 2003, 421 (6925) :844-848
[20]  
Kobayashi M, 2003, J NEUROSCI, V23, P2440