Neuregulin 1 Deficiency Modulates Adolescent Stress-Induced Dendritic Spine Loss in a Brain Region-Specific Manner and Increases Complement 4 Expression in the Hippocampus

David J Clarke; Tariq W Chohan; Mustafa S Kassem; Kristie L Smith; Rose Chesworth; Tim Karl; Michael P Kuligowski; Sandra Y Fok; Maxwell R Bennett; Jonathon C Arnold

doi:10.1093/schbul/sby029

Neuregulin 1 Deficiency Modulates Adolescent Stress-Induced Dendritic Spine Loss in a Brain Region-Specific Manner and Increases Complement 4 Expression in the Hippocampus

Schizophr Bull. 2019 Mar 7;45(2):339-349. doi: 10.1093/schbul/sby029.

Authors

David J Clarke^{1

2}, Tariq W Chohan^{1

2}, Mustafa S Kassem¹, Kristie L Smith¹, Rose Chesworth³, Tim Karl^{3

4

5}, Michael P Kuligowski⁶, Sandra Y Fok¹, Maxwell R Bennett¹, Jonathon C Arnold^{1

2}

Affiliations

¹ Brain and Mind Centre, University of Sydney, Sydney, Australia.
² Department of Pharmacology, University of Sydney, Sydney, Australia.
³ School of Medicine, Western Sydney University, Sydney, Australia.
⁴ Neuroscience Research Australia, Randwick, Australia.
⁵ School of Medical Sciences, University of New South Wales, Sydney, Australia.
⁶ Australian Microscopy & Microanalysis Research Facility, University of Sydney, Camperdown, Australia.

Abstract

One neuropathological feature of schizophrenia is a diminished number of dendritic spines in the prefrontal cortex and hippocampus. The neuregulin 1 (Nrg1) system is involved in the plasticity of dendritic spines, and chronic stress decreases dendritic spine densities in the prefrontal cortex and hippocampus. Here, we aimed to assess whether Nrg1 deficiency confers vulnerability to the effects of adolescent stress on dendritic spine plasticity. We also assessed other schizophrenia-relevant neurobiological changes such as microglial cell activation, loss of parvalbumin (PV) interneurons, and induction of complement factor 4 (C4). Adolescent male wild-type (WT) and Nrg1 heterozygous mice were subjected to chronic restraint stress before their brains underwent Golgi impregnation or immunofluorescent staining of PV interneurons, microglial cells, and C4. Stress in WT mice promoted dendritic spine loss and microglial cell activation in the prefrontal cortex and the hippocampus. However, Nrg1 deficiency rendered mice resilient to stress-induced dendritic spine loss in the infralimbic cortex and the CA3 region of the hippocampus without affecting stress-induced microglial cell activation in these brain regions. Nrg1 deficiency and adolescent stress combined to trigger increased dendritic spine densities in the prelimbic cortex. In the hippocampal CA1 region, Nrg1 deficiency accentuated stress-induced dendritic spine loss. Nrg1 deficiency increased C4 protein and decreased C4 mRNA expression in the hippocampus, and the number of PV interneurons in the basolateral amygdala. This study demonstrates that Nrg1 modulates the impact of stress on the adolescent brain in a region-specific manner. It also provides first evidence of a link between Nrg1 and C4 systems in the hippocampus.

Keywords: amygdala; microglia; parvalbumin; prefrontal cortex; restraint; schizophrenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amygdala* / metabolism
Amygdala* / pathology
Animals
Cerebral Cortex* / metabolism
Cerebral Cortex* / pathology
Complement C4 / metabolism*
Dendritic Spines / pathology*
Disease Models, Animal
Interneurons / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microglia / metabolism*
Neuregulin-1 / deficiency*
Parvalbumins / metabolism
Random Allocation
Resilience, Psychological*
Stress, Psychological* / metabolism
Stress, Psychological* / pathology

Substances

Complement C4
Neuregulin-1
Nrg1 protein, mouse
Parvalbumins