Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system

Abstract

Neuregulin-1 (NRG1) and its ErbB2/B4 receptors are encoded by candidate susceptibility genes for schizophrenia, yet the essential functions of NRG1 signaling in the CNS are still unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. In contrast to expectations, cell layers in the cerebral cortex, hippocampus, and cerebellum develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs dendritic spine maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote spine maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition. Treatment with the antipsychotic drug clozapine reverses the behavioral and spine defects. We conclude that ErbB2/B4-mediated NRG1 signaling modulates dendritic spine maturation, and that defects at glutamatergic synapses likely contribute to the behavioral abnormalities in ErbB2/ B4-deficient mice.cerebral cortex ͉ dendritic spines ͉ migration ͉ neuregulin ͉ schizophrenia N RG1 activates receptor tyrosine kinases consisting of dimers formed by ErbB2, ErbB3, and ErbB4. Both ErbB3 and ErbB4 bind NRG1, whereas ErbB2 and ErbB4 have intrinsic tyrosine kinase activity. Functional NRG1 receptors therefore consist of ErbB4 homodimers, or of heterodimers between ErbB2, ErbB3 and ErbB4 (1). NRG1 and its receptors are expressed in the CNS and the NRG1, ErbB2, and ErbB4 genes are candidate susceptibility genes for schizophrenia (1, 2). In the central nervous system (CNS), NRG1 is thought to regulate the differentiation of radial glia and neurons, myelination, neuronal migration and synaptic function (1). However, mice with targeted deletions of NRG1, ErbB2 and ErbB4 die during embryogenesis, whereas mice lacking ErbB3 die perinatally (3-6). Thus, our knowledge of NRG1-ErbB functions in the CNS has been derived from studies using cultured cells, dominantnegative ErbB receptors, and mice partially defective in NRG1 signaling (1). No animal model lacking all NRG1 signaling specifically in the CNS has been described. We have therefore engineered ErbB2/B4-CNSko mice that lack both ErbB2 and ErbB4 (the only ErbBs with intrinsic tyrosine kinase activity) in the CNS. Surprisingly, the mutant mice show no defects in brain morphology and in the layered structure of the cerebral cortex, hippocampus, and cerebellum. Instead, the maturation of dendritic spines is affected. ErbB2/B4-deficient mice also display behavioral abnormalities that have been associated with schizophrenia-like symptoms. Clozapine treatment reverses behavioral and spine defects, indicating that perturbation of glutamatergic synapses might contribute to the behavioral abnormalities. Interestingly, reduced spine density has been observed in the brain of schizophrenia patients (7), suggesting that defects in spine maturation may constitute a risk factor for the development of schizophrenia. ResultsNormal Cortical Development and Glial-Guided Migration. To inactivate NR...

Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex

“…According to previous studies, NRG1 exerts different trophic effects on cortical GABAergic interneurons depending on the length of exposure to the neurotrophic factor Barros et al, 2009;Fisahn et al, 2009;Fazzari et al, 2010). Acute effects include NRG1-triggered GABA release, which involves an increase in membrane excitability in presynaptic terminals Wen et al, 2010).…”

Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

“…Impaired lateral inhibition in NRG1 Ig-like domain mutant mice could also be improved by clozapine (Rimer et al, 2005). In addition, clozapine could reverse the abnormalities in ErbB4-deficient mice, including decreased anxiety in the open field test, more aggressive activities in the resident-intruder assay and lower PPI level (Barros et al, 2009).…”

“…In the last decade, animal studies have shown that animals with abnormal NRG1-ErbB4 functions display schizophrenia-like behavioural abnormalities, including hyperactivities in the novel open-field test and the alternating-Y maze (Barros et al, 2009;Duffy et al, 2008;Gerlai et al, 2000;O'Tuathaigh et al, 2007;Rimer et al, 2005;Stefansson et al, 2002;van den Buuse et al, 2009), deficits in prepulse inhibition (PPI) level (Barros et al, 2009;Dejaegere et al, 2008;Hong et al, 2008;Savonenko et al, 2008;Stefansson et al, 2002;van den Buuse et al, 2009), and lateral inhibition (Rimer et al, 2005), as well as impaired social activities (O'Tuathaigh et al, 2007). These reports provided evidence supporting the potential roles of mutations in NRG1 and ErbB4 genes as risk factors for schizophrenia.…”

“…NRG1-induced stimulation of the ErbB4 receptor plays critical roles in the neuronal functions that are closely related to the development of schizophrenia, mainly neuronal specification, neuronal migration, neuron-glial signalling, synapse formation, synaptic transmission, and plasticity of the CNS (for review: see Harrison and Law, 2006). Several studies found that animals with impaired NRG1-ErbB4 signalling displayed schizophrenia-like behavioural abnormalities (Barros et al, 2009;Dejaegere et al, 2008;Rimer et al, 2005;Savonenko et al, 2008;Stefansson et al, 2002).…”

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

“…Furthermore, clozapine and haloperidol could improve PPI (prepulse inhibition) deficits in NRG1 and ErbB4 knock-out mice (Barros et al, 2009;Dejaegere et al, 2008;Savonenko et al, 2008); therefore the effects of haloperidol on the expression of NRG1 and ErbB4 observed in this study may provide a mechanism for this behavioural effect.…”