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

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.

Long term effects of peripubertal stress on excitatory and inhibitory circuits in the prefrontal cortex of male and female mice

“…The data from animals stressed during the peripubertal period is also heterogenous. Our data indicating a lack of difference in the number of PV expressing interneurons in the mPFC of male mice is in agreement with studies using a combination of social isolation and forced swimming ( Page et al, 2018 ) or chronic restraint stress ( Clarke et al, 2019 ). However, another study, using a combination of physical stressors during the adolescence found a reduction in the density of PV + cells in the PrL, although only in male mice ( Page and Coutellier, 2018 ); no differences were detected in the IL cortex or when analyzing females (although the estrous cycle phase was not controlled at sacrifice).…”

Inhibiting Brd4 alleviated PTSD‐like behaviors and fear memory through regulating immediate early genes expression and neuroinflammation in rats

“…However, IFS failed to change microglial activation and levels of pro‐inflammatory cytokines and NF‐κB in amygdala in this study. This might be because of an area‐specific response to stressors (Clarke et al., 2019; Li et al., 2021; Smith et al., 2019) on the one hand and on the other hand, the results implicated that activating of microglia and releasing of pro‐inflammatory cytokines could not interpret all symptoms of PTSD.…”

Early neuroadaptations to an obesogenic diet identify the schizophrenia-related ErbB4 receptor in obesity-induced hippocampal abnormalities

“…NRG1 signaling participates in several critical neurodevelopmental processes and is implicated in nerve cell differentiation and synapse formation, radial glia formation and neuronal migration, axon navigation, and neurite outgrowth (Mei and Nave, 2014). Perturbations in NRG1/ErbB4 function have been associated with various neuropsychiatric disorders (Mei and Nave, 2014), resilience to stress (Clarke et al, 2018), and obesity/metabolic syndrome (Ennequin et al, 2015a; Salinas et al, 2016; Zeng et al, 2018; Zhang et al, 2018). Emerging evidence suggests that ErbB4 may also be important in the pathogenesis of obesity in humans (Locke et al, 2015; Salinas et al, 2016).…”

“…Perturbations in NRG1/ErbB4 function have been associated with various neuropsychiatric disorders (Mei and Nave, 2014), resilience to stress (Clarke et al, 2018), and obesity/metabolic syndrome (Ennequin et al, 2015a;Salinas et al, 2016;Zeng et al, 2018;Zhang et al, 2018). Emerging evidence suggests that ErbB4 may also be important in the pathogenesis of obesity in humans (Locke et al, 2015;Salinas et al, 2016).…”

“…NRG1-ErbB4 signaling has been heavily implicated in neuronal migration, synaptic plasticity, and cognition (Mei and Xiong, 2008). NRG1-ErbB4 signaling regulates hippocampal function through increasing neuronal arborization (Gerecke et al, 2004), increasing gamma oscillations in the CA3 region of the hippocampus (Fisahn et al, 2009), modulating long-term potentiation at CA1 hippocampal synapses (Kwon et al, 2008), and modifying stress reactivity and behavior (Dang et al, 2016;Mahar et al, 2017;Clarke et al, 2018). Exogenous NRG1 administration increases hippocampal neurogenesis (Mahar et al, 2011(Mahar et al, , 2016 and improves learning and memory while rescuing dendritic and synaptic abnormalities in a mouse model of Alzheimer's disease (AD) (Ryu et al, 2016).…”