Neuregulin 1 and ErbB4 Kinase Actively Regulate Sharp Wave Ripples in the Hippocampus

Abstract

Sharp wave ripples (SW-Rs) in the hippocampus are synchronized bursts of hippocampal pyramidal neurons (PyNs), critical for spatial working memory. However, the molecular underpinnings of SW-Rs remain poorly understood. We show that SW-Rs in hippocampal slices from both male and female mice were suppressed by neuregulin 1 (NRG1), an epidermal growth factor whose expression is enhanced by neuronal activity. Pharmacological inhibition of ErbB4, a receptor tyrosine kinase for NRG1, increases SW-R occurrence rate in hippocampal slices. These results suggest an important role of NRG1-ErbB4 signaling in regulating SW-Rs. To further test this notion, we characterized SW-Rs in freely moving male mice, chemical genetic mutant mice, where ErbB4 can be specifically inhibited by the bulky inhibitor 1NMPP1. Remarkably, SW-R occurrence was increased by 1NMPP1. We found that 1NMPP1 increased the firing rate of PyN neurons, yet disrupted PyN neuron dynamics during SW-R events. Furthermore, 1NMPP1 increased SW-R occurrence during both nonrapid eye movement (NREM) sleep states and wake states with a greater impact on SW-Rs during wake states. In accord, spatial working memory was attenuated in male mice. Together these results indicate that dynamic activity of ErbB4 kinase is critical to SW-Rs and spatial working memory. This study reveals a novel regulatory mechanism of SW-Rs and a novel function of the NRG1-ErbB4 signaling.

Neuregulins: subcellular localization, signaling pathways and their relationship with neuroplasticity and neurological diseases

“…Additionally, the BBB is affected after BT, exposing the brain to inflammation. In adult rodents, NRG1 crossed the intact BBB activating midbrain ErbB4 receptors by phosphorylation, increasing DA levels in the substantia nigra and striatum [154,158], and exerting beneficial effects on endothelial permeability and BBB permeability after BT [159]. This evidence shows the potential of NRG as a neuroprotective factor to induce neurological recovery after brain injury.…”

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression

“…This analysis revealed that FSI in the App NL-G-F group at P60 had distinctive intrinsic properties since they clustered in a separate area of the plot compared to the App NL-G-F group at P30 and the WT groups at P30 and P60 (Fig Moreover, we found that the synaptic pathways were scarcely affected by maturation to these pathways were selected based on their involvement in gamma oscillations and FSI functionality as potential causes of early functional impairment during amyloid pathology progression. Kcnc1 [45][46][47], Kcns3 [48,49], Scn1a [50,51], Erbb4 [52][53][54][55],…”

microRNA-dependent regulation of gene expression in GABAergic interneurons

“…Finally, alterations in neuregulin1 (NRG1)-ErbB4 signaling have been demonstrated to alter memory performance. However, depending on the model, ablating ErbB4 in PV INs of hippocampal CA1 either enhance (Tian et al, 2017) or impair (Robinson et al, 2022) spatial and working memory performance.…”