Partial genetic deletion of neuregulin 1 modulates the effects of stress on sensorimotor gating, dendritic morphology, and HPA axis activity in adolescent mice.
Stress has been linked to the pathogenesis of schizophrenia. Genetic variation in neuregulin 1 (NRG1) increases the risk of developing schizophrenia and may help predict which high-risk individuals will transition to psychosis. NRG1 also modulates sensorimotor gating, a schizophrenia endophenotype. We used an animal model to demonstrate that partial genetic deletion of Nrg1 interacts with stress to promote neurobehavioral deficits of relevance to schizophrenia. Nrg1 heterozygous (HET) mice displayed greater acute stress-induced anxiety-related behavior than wild-type (WT) mice. Repeated stress in adolescence disrupted the normal development of higher prepulse inhibition of startle selectively in Nrg1 HET mice but not in WT mice. Further, repeated stress increased dendritic spine density in pyramidal neurons of the medial prefrontal cortex (mPFC) selectively in Nrg1 HET mice. Partial genetic deletion of Nrg1 also modulated the adaptive response of the hypothalamic-pituitary-adrenal axis to repeated stress, with Nrg1 HET displaying a reduced repeated stress-induced level of plasma corticosterone than WT mice. Our results demonstrate that Nrg1 confers vulnerability to repeated stress-induced sensorimotor gating deficits, dendritic spine growth in the mPFC, and an abberant endocrine response in adolescence.
The Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, NSW 2006, Australia;
Tariq W
TW
Chohan
The Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia;
Aurelie A
AA
Boucher
The Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, NSW 2006, Australia;
Jarrah R
JR
Spencer
The Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia;
Mustafa S
MS
Kassem
Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, NSW 2006, Australia;
Areeg A
AA
Hamdi
Neuroscience Research Australia, Randwick, NSW 2031, Australia.
Tim
T
Karl
The Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia;
Sandra Y
SY
Fok
The Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia;
Maxwell R
MR
Bennett
The Brain and Mind Research Institute, University of Sydney, Sydney, NSW 2006, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, NSW 2006, Australia; jonathon.arnold@sydney.edu.au.
Jonathon C
JC
Arnold
D000818:Animals; D049229:Dendritic Spines; D004195:Disease Models, Animal; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020890:Neuregulin-1 / Q000235:genetics / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000166:cytology*; D065808:Prepulse Inhibition / Q000502:physiology; D055139:Sensory Gating / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology*
D020890:Neuregulin-1
PPI; adolescence; dendritic morphology; neuregulin 1; schizophrenia; stress