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 tm1.1Lwrϩ/Ϫ ) 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.

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

“…Polymorphisms in the secreted growth factor neuregulin 1 (NRG1) have been associated with risk for schizophrenia (2)(3)(4) and recently, common genetic variation and structural microdeletions in ErbB4, a receptor tyrosine kinase for NRG1, have also been associated with the disorder (5-9). NRG1-ErbB4 signaling plays a critical role in neural development and synaptic plasticity (10)(11)(12) and NRG1 and ErbB4 mutant mice exhibit behavioral alterations (2,(12)(13)(14) consistent with other murine models of schizophrenia (15). Schizophrenia-associated genetic variation in these genes is implicated in human brain structure and function (6,16,17), but the biological mechanisms accounting for these diverse effects and how they translate into illness are unclear.…”

Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

“…Accordingly, various exons of the NRG1 genome have been disrupted by homologous recombination in mice and their neurobehavioral traits have been investigated. 1,[16][17][18][19] In adults, the mutant mice of NRG1 variants often exhibit schizophrenia-associated behavioral abnormalities. As hypomorphic or hypermorphic NRG1 signals persists throughout life in these genetic mutants (that is, is not temporally controlled), the evaluation of these models is challenging in regard to the neurodevelopmental hypothesis.…”

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

“…In mouse models, behavioral signs of schizophrenia are found in mice heterozygous for Nrg1 or Erbb4 (refs. 14,[25][26][27] and also in mice overexpressing NRG1 selectively in the brain 28,29 . In studies of schizophrenic individuals, NRG1 expression is increased in both the cortex 30 and hippocampus 31 , where NRG1-ErbB4 signaling is excessive 12,31 .…”