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Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components.

ABSTRACT: Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we studied the regulation of type III Nrg1 expression and evaluated the effect of decreased expression of the type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus, and ventral subiculum, regions involved in the regulation of sensorimotor gating and short-term memory. Adult heterozygous mutant mice with a targeted disruption for type III Nrg1 (Nrg1(tm1.1Lwr+/-)) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. Magnetic resonance imaging of type III Nrg1 heterozygous mice revealed hypofunction in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between type III Nrg1 heterozygous mice and their wild-type littermates. Our findings demonstrate a role of type III Nrg1 signaling in the maintenance of corticostriatal components and in the neural circuits involved in sensorimotor gating and short-term memory.

SUBMITTER: Chen YJ

PROVIDER: S-EPMC2728592 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components.

Chen Ying-Jiun J YJ Johnson Madeleine A MA Lieberman Michael D MD Goodchild Rose E RE Schobel Scott S Lewandowski Nicole N Rosoklija Gorazd G Liu Ruei-Che RC Gingrich Jay A JA Small Scott S Moore Holly H Dwork Andrew J AJ Talmage David A DA Role Lorna W LW

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080701 27

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we studied the regulation of type III Nrg1 expression and evaluated the effect of decreased expression of the type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult b ...[more]

PMID: 18596162

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Project description:BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

Dataset Information

Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components.

Publications

Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components.

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