Seminar

Neuregulin-1 Signaling & Schizophrenia: neural connections misbehaving

Internal Seminar Claudia S. Barros, PhD

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 central nervous system (CNS) remain unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. Surprisingly, cortical cell layers develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs synapse maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote synapse maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition, behavioral defects associated with schizophrenia-like symptoms. Treatment with the antipsychotic drug Clozapine ameliorates both behavioral and postsynaptic defects. In conclusion, ErbB2/B4-mediated NRG1 signaling modulates synapse maturation. Defects in this process likely contribute to the behavioral abnormalities in ErbB2/B4-deficient mice and may constitute a risk factor for schizophrenia development.