Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Abstract

Summary Neuregulin 1 (Nrg1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here we show that ctoNrg1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice that had been symptomatic, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a novel pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling.

VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function

“…To quantify the number of DA (TH + ) or NeuN + neurons in SNpc, the unbiased stereological estimation of the total number of the TH + /NeuN + cells in VM (ventral midbrain) was employed as previously described (Yin et al, 2013). In brief, every fifth section from the bregma −2.92 to −4.16 mm coronal sections across the midbrain were stained with TH/NeuN antibody.…”

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…In terms of increased Nrg1 signaling, transgenic mice overexpressing neuronal Nrg1 Type I exhibited hyperactivity, reduced PPI, impaired working memory, contextual fear conditioning and social interaction (Deakin et al, 2009; Deakin et al, 2012; Kato et al, 2010; Luo et al, 2013; Yin et al, 2013a). Importantly, switching off Nrg1 expression in pyramidal neurons of adult mice diminishes behavioral deficits and synaptic dysfunction (Luo et al, 2013; Yin et al, 2013a).…”

“…Importantly, switching off Nrg1 expression in pyramidal neurons of adult mice diminishes behavioral deficits and synaptic dysfunction (Luo et al, 2013; Yin et al, 2013a). This provides compelling evidence that high levels of Nrg1 are pathogenic and suggests that effects of abnormal development can be overcome.…”

“…This provides compelling evidence that high levels of Nrg1 are pathogenic and suggests that effects of abnormal development can be overcome. Conversely, increase of Nrg1 in adult mice appears to be sufficient to impair glutamatergic transmission and behavior (Yin et al, 2013a; Agarwal et al, 2014). These observations suggest that overexpression-induced deficits require continuous Nrg1 abnormality in adulthood and that schizophrenia patients might benefit from a therapeutic adjustment of NRG1 signaling.…”

“…For example, elevated Erbb4 levels increase the spine density in neonatal, organotypic hippocampal slices (Li et al, 2007). LIM kinase 1 (Limk1) is recruited into synaptosomes following overexpression of Nrg1 (Yin et al, 2013a). LIMK1 is among the 25 genes deleted in Williams syndrome (Tassabehji et al, 1996), and the gene is duplicated in some patients with autism (Sanders et al, 2011) or SZ (Kirov et al, 2012).…”