Neuregulin 1 and ErbB4 kinase actively regulate sharp wave ripples in the hippocampus.

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 non rapid eye movement sleep (NREM) 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.SIGNIFICANCE STATEMENTSW-Rs are a hippocampal event, important for memory functioning. Yet the molecular pathways that regulate SW-Rs remain unclear. NRG1, previously known to be increased in PyN in an activity dependent manner, signals to its receptor, ErbB4 kinase, that is in important regulator of GABAergic transmission and long-term potentiation in the hippocampus. Our findings demonstrate that SW-Rs are regulated by this signaling pathway in a dynamic manner. Not only so, we show that this signaling pathway is dynamically needed for spatial working memory. These data suggest a molecular signaling pathway, NRG1-ErbB4 that regulates an important network event of the hippocampus, SW-Rs, that underlies memory functioning.