Ablation of ErbB4 in parvalbumin‐positive interneurons inhibits adult hippocampal neurogenesis through down‐regulating BDNF/TrkB expression

Abstract

Parvalbumin (PV) positive interneurons in the subgranular zone (SGZ) can regulate adult hippocampal neurogenesis. ErbB4 is mainly expressed in PV neurons in the hippocampus and is crucial for keeping normal function of PV neurons. However, whether ErbB4 in PV interneurons affects the adult hippocampal neurogenesis remains unknown. In the present study, we deleted ErbB4 specifically in PV neurons by crossing PV‐Cre mice with ErbB4f/f mice. Results of BrdU labeling and NeuN staining revealed that the proliferation of neural progenitors was increased but the survival and maturation of newborn neurons were decreased in the hippocampus of mice after deleting ErbB4 in PV neurons, suggesting that ErbB4 in PV neurons is closely associated with the process of adult hippocampal neurogenesis. Interestingly, the expression of brain‐derived neurotrophic factor (BDNF) and its receptor, tropomyosin‐related kinase B (TrkB), was significantly decreased in the hippocampus of ErbB4‐deleted mice. Together, our data suggested that ErbB4 in PV neurons might modulate adult hippocampal neurogenesis by affecting BDNF–TrkB signaling pathway.

Parvalbumin Interneuron Activation-Dependent Adult Hippocampal Neurogenesis Is Required for Treadmill Running to Reverse Schizophrenia-Like Phenotypes

“…The membrane and cytoplasm of PV interneurons in the DG of control mice were strongly immunoreactive by immunostaining, having a fusiform or elliptical shape ( Figure 6E). Post hoc analysis revealed that ErbB4 ablation significantly decreased PV-positive cells number (Figure 6F), which is in line with previous reports (Chen et al, 2010;Tian et al, 2017;Zhang et al, 2018). PV-ErbB4 −/− mice subjected to treadmill running (PV-ErbB4 −/− + run) increased the number of PV-positive interneurons when compared to those corresponding model mice (PV-ErbB4 −/− + static) ( Figure 6F).…”

“…PV-ErbB4 −/− mice subjected to treadmill running (PV-ErbB4 −/− + run) increased the number of PV-positive interneurons when compared to those corresponding model mice (PV-ErbB4 −/− + static) ( Figure 6F). ErbB4 ablation in PV interneurons sharply increase the proliferation of NSCs in the hippocampus (Figures 6G,H), in line with previous reports using BrdU labeling (Zhang et al, 2018). Moreover, PV-ErbB4 −/− mice subjected to treadmill running significantly increased the number of Ki67-positive cells in the DG (Figure 6H).…”

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

“…Furthermore, citalopram administration decreases the quantity of newly generated Aβ in young healthy humans (Sheline et al, 2014). Clinical studies indicate that citalopram has therapeutic effects in AD patients, including rescuing non-cognitive neuropsychiatric behaviors such as depression, anxiety, irritability, and apathy (Zhang H. et al, 2018), although the benefits on agitation and cognition remain controversial (Siddique et al, 2009;Porsteinsson et al, 2014). Results from socially isolated rats suggested that citalopram improves learning and memory by promoting synaptic plasticity and hippocampal neurogenesis (Gong et al, 2017).…”

“…Recent studies demonstrated that ErbB4 protein knockdown in PV inhibitory interneurons significantly increased LTP and improved memory ability in hAPP-J20 mice without changing Aβ plaque deposition (Zhang et al, 2017). One plausible mechanism for this is that ErbB4 ablation increases PV inhibitory interneuron activity (Zhang et al, 2017;Zhang H. et al, 2018), although this requires further confirmation. By regulating GAD67 expression in GABA inhibitory interneurons, half-quantity expression of GAD67 significantly reduced Aβ deposition and improved cognitive performance in 5xFAD mice due to elevated GABA inhibitory interneuron activity (Wang et al, 2017a).…”

Treadmill Running Regulates Adult Neurogenesis, Spatial and Non-Spatial Learning by ErbB4 Signaling

“…Neurotrophic factor neuregulin 1 and its receptor ErbB4 are susceptibility genes of schizophrenia and bipolar disorders [8,9]. ErbB4 is exclusively expressed in GABAergic interneurons in hippocampus, and mainly in parvalbumin positive type, regulating the spine formation and synaptic plasticity in glutamatergic neurons [10,11], specifically knockout ErbB4 in parvalbumin interneurons is enough to induce cognitive impairments and inhibits adult hippocampus neurogenesis [12]. Exercise can increase neuregulin 1/ErbB signaling in skeletal and cardiac muscle and promote muscle repairment [13,14], we also observed exercise could increase ErbB4 expression in hippocampus, but whether neuregulin1/ErbB signaling mediates exercise effects on adult neurogenesis is still unknown.…”