TY - JOUR
T1 - Reduced conditioned fear response in mice that lack Dlx1 and show subtype-specific loss of interneurons
AU - Mao, Rong
AU - Page, Damon T.
AU - Merzlyak, Irina
AU - Kim, Carol
AU - Tecott, Laurence H.
AU - Janak, Patricia H.
AU - Rubenstein, John L.R.
AU - Sur, Mriganka
N1 - Funding Information:
Acknowledgements This work was supported by funds to M.S. (Simons Foundation and the Autism Consortium), R.M. (National Eye Institute Kirschstein-NRSA Fellowship 1 F32 EY017243), D.T.P. (Nancy Lurie Marks Family Foundation), P.H.J. (funds from the state of California), and J.L.R.R. (Nina Ireland and NIMH R37 Grant MH049428). We thank Jed Holtzman and Luna Abdallah for assistance in studies on mouse general activity levels, Li-Huei Tsai, Ji-Song Guan, and Andre Fischer for advice and assistance in fear conditioning assays, Orsolya Kuti for help in maintaining mouse colonies, Yuri Ostrovsky and Cortina McCurry for insightful discussion on data analysis. We are grateful to Sonal Jhaveri for valuable comments on the manuscript.
PY - 2009
Y1 - 2009
N2 - The inhibitory GABAergic system has been implicated in multiple neuropsychiatric diseases such as schizophrenia and autism. The Dlx homeobox transcription factor family is essential for development and function of GABAergic interneurons. Mice lacking the Dlx1 gene have postnatal subtype-specific loss of interneurons and reduced IPSCs in their cortex and hippocampus. To ascertain consequences of these changes in the GABAergic system, we performed a battery of behavioral assays on the Dlx1 mutant mice, including zero maze, open field, locomotor activity, food intake, rotarod, tail suspension, fear conditioning assays (context and trace), prepulse inhibition, and working memory related tasks (spontaneous alteration task and spatial working memory task). Dlx1 mutant mice displayed elevated activity levels in open field, locomotor activity, and tail suspension tests. These mice also showed deficits in contextual and trace fear conditioning, and possibly in prepulse inhibition. Their learning deficits were not global, as the mutant mice did not differ from the wild-type controls in tests of working memory. Our findings demonstrate a critical role for the Dlx1 gene, and likely the subclasses of interneurons that are affected by the lack of this gene, in behavioral inhibition and associative fear learning. These observations support the involvement of particular components of the GABAergic system in specific behavioral phenotypes related to complex neuropsychiatric diseases.
AB - The inhibitory GABAergic system has been implicated in multiple neuropsychiatric diseases such as schizophrenia and autism. The Dlx homeobox transcription factor family is essential for development and function of GABAergic interneurons. Mice lacking the Dlx1 gene have postnatal subtype-specific loss of interneurons and reduced IPSCs in their cortex and hippocampus. To ascertain consequences of these changes in the GABAergic system, we performed a battery of behavioral assays on the Dlx1 mutant mice, including zero maze, open field, locomotor activity, food intake, rotarod, tail suspension, fear conditioning assays (context and trace), prepulse inhibition, and working memory related tasks (spontaneous alteration task and spatial working memory task). Dlx1 mutant mice displayed elevated activity levels in open field, locomotor activity, and tail suspension tests. These mice also showed deficits in contextual and trace fear conditioning, and possibly in prepulse inhibition. Their learning deficits were not global, as the mutant mice did not differ from the wild-type controls in tests of working memory. Our findings demonstrate a critical role for the Dlx1 gene, and likely the subclasses of interneurons that are affected by the lack of this gene, in behavioral inhibition and associative fear learning. These observations support the involvement of particular components of the GABAergic system in specific behavioral phenotypes related to complex neuropsychiatric diseases.
KW - Associative learning
KW - Behavior
KW - Calretinin
KW - Fear conditioning
KW - GABAergic
KW - Hyperactivity
KW - Inhibitory
KW - Interneuron
KW - Neuropsychiatric disease
KW - Prepulse inhibition
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U2 - 10.1007/s11689-009-9025-8
DO - 10.1007/s11689-009-9025-8
M3 - Article
AN - SCOPUS:77949375239
SN - 1866-1947
VL - 1
SP - 224
EP - 236
JO - Journal of Neurodevelopmental Disorders
JF - Journal of Neurodevelopmental Disorders
IS - 3
ER -