Specialized Information Processing Deficits and Distinct Metabolo.pdf (1.26 MB)
Download file

Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1

Download (1.26 MB)
journal contribution
posted on 2022-03-07, 12:24 authored by Colm MP O'Tuathaigh, Naina Mathur, Matthew J. O'Callaghan, Lynsey MacIntyre, Richard Harvey, Dona Lai, John WaddingtonJohn Waddington, Bemjamom S. Pickard, David D. Watson, Paula M. Moran

Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across 2 different sites and protocols, Nrg1 mutants demonstrated deficits in prepulse inhibition, a measure of sensorimotor gating, that is, disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in a “what–where–when” object recognition memory task, Nrg1 mutants displayed sex-specific (males only) disruption of “what– when” performance, indicative of impaired temporal aspects of episodic memory. Differential metabolomic profiling revealed that these behavioral phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioral changes in adulthood.



The original article is available at https://academic.oup.com/

Published Citation

O'Tuathaigh CMP, Mathur N, O'Callaghan MJ, MacIntyre L, Harvey R, Lai D, et al. Schizophrenia Bulletin. 2017; 43(5):1100-1113

Publication Date



  • School of Pharmacy and Biomolecular Sciences