Neuregulin-1 signalling and antipsychotic treatment

Abstract

Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects.

Disrupted hippocampal neuregulin-1/ErbB3 signaling and dentate gyrus granule cell alterations in suicide

“… 13 , 31 , 32 , 33 , 34 Although previously considered to be kinase-insufficient (c.f. Cao et al 35 ) based largely on a report of reduced autophosphorylation compared to EGFR in insect cells with induced ErbB3 expression, 36 recent studies have suggested that ErbB3 has sufficient kinase activity for signaling, 37 , 38 , 39 and its downstream signaling primarily involves PI3K/AKT. 40 ErbB3 has also recently been found to be required for certain types of cell proliferation in the brain, likely due to downstream PI3K signaling.…”

Neuregulin-1 alpha, the underestimated molecule: emerging new roles in normal brain function and the pathophysiology of schizophrenia?

“…The latter aspect is of special relevance for all those interested in NRG-1 function in the brain. Although there is paramount evidence in favour of a central role of NRG-1 in normal brain development, adult brain function, and the pathophysiology of various brain diseases (reviewed in Deng et al 2013), amazingly little is known about cerebral NRG-1␣. Some years ago we and others have demonstrated that NRG-1␣ is expressed in rat, monkey, and human brain, showing a remarkable regional and cellular distribution pattern (Bernstein et al 2006;Connor et al 2009).…”

Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation

“…Of the multiple members of the neuregulin family that bind with ErbB4, NRG-1 is the most strongly linked to schizophrenia at this time (Buonanno, 2010), though some studies indicate mutations of NRG-3 may increase risk as well (Kao et al, 2010). Neuregulin-1 has numerous different isoforms via various promoters and alternative splicing (Buonanno and Fischbach, 2001; Deng et al, 2013; Seroogy et al, 2013), and in our study we used a pan-NRG-1 probe to detect expression of multiple forms of NRG-1. It is possible that a riboprobe targeting more specific isoforms would uncover more subtle variations in NRG-1 gene expression.…”