Piezo2, a pressure sensitive channel is expressed in select neurons of the mouse brain: a putative mechanism for synchronizing neural networks by transducing intracranial pressure pulses

Abstract

Piezo2 expression in the normal, young adult mouse brain was examined using an anti-PIEZO2 Ab generated against a C-terminal fragment of the human PIEZO2 protein. As a positive control for Ab staining of mouse neurons, the Ab was shown to stain the majority (~90%) of mouse dorsal root ganglia (DRG) neurons, consistent with recent in situ hybridization and transcriptomic studies that also indicate Piezo2 gene expression in ~90% mouse DRG neurons.As a negative control and stringent test for specificity, the Ab failed to stain DRG satellite glial cells, which do not express Piezo2 but rather its paralog, Piezo1. In slices of brains isolated from the same mice as the DRG, the Ab displayed high selectivity in staining only specific neuron types, including some pyramidal neurons in the neocortex and hippocampus, Purkinje cells in the cerebellar cortex, and most notably mitral cells within the olfactory bulb. Given the demonstrated role of Piezo2 channels in peripheral neurons as a low-threshold pressure sensor (i.e., ≤ 5 mm Hg) critical for gentle touch, proprioception, and the regulation of breathing and blood pressure, its expression in select brain neurons has interesting implications. In particular, we propose that the pressure sensitive channel may provide specific brain neurons with an intrinsic resonance that acts to synchronize their firing with the normal pulsatile changes in intracranial pressure (ICP) associated with breathing and cardiac cycles. This novel mechanism could serve to increase the robustness of the respiration entrained oscillations that have been recorded in both rodent and human brains across widely distributed neuronal networks. The idea of a "global rhythm" within the brain has been mainly related to the effect of nasal airflow activating mechanosensitive neurons within the olfactory epithelium, which in turn synchronize, through direct synaptic connections, mitral neurons within the olfactory bulb and then through their projections, the activity of neural networks in other brain regions, including the hippocampus and neocortex. Our proposed, non-synaptic, intrinsic resonance mechanism for tracking pulsatile ICP changes would have the advantage that spatially separated brain networks could be globally synchronized effectively at the speed of sound.

Piezo2 mechanosensitive ion channel is located to sensory neurons and non-neuronal cells in rat peripheral sensory pathway: implications in pain

“…We also detected extensive Piezo2 expression in rat brain neurons, consistent with a recent independent report showing Piezo2 expression in adult mouse brain neurons [69]. It is not wholly surprising to identify Piezo2 in brain since the Piezo gene is originally discovered in brain and dubbed as Mib (Membrane protein induced by Aβ) [55]; and study using brain neuronal analogue N2A cells discovers Mib as a mechanosensor and subsequently renamed as Piezo2 [15].…”

“…Similarly, single-cell RT-PCR reports that Piezo2 mRNA is detected in 39% of all DRG-PSNs, while new efforts by single-cell RNA sequencing (RNAseq) identify Piezo2 in the majority of mouse DRG-PSNs [51, 72, 83]. Immunohistochemistry (IHC) has observed Piezo2 expression in up to 45∼80% of total PSNs of mouse DRG with high expression in large diameter PSNs, while a recent report describes Piezo2 expression in all PSNs of mouse DRG neurons, including large-diameter myelinated neurons encompassing LTMRs, as well as medium- and small-diameter nociceptors [43, 62, 69, 73]. These reports of Piezo2 expression in ganglia are derived from mouse or duck [56], but Piezo2 expression has not been systematically examined in the rat peripheral nervous system (PNS).…”

Spike-frequency dependent inhibition and excitation of neural activity by high-frequency ultrasound

“…Mechanical effects of radiation force could also affect channels besides K2P channels. The mechanically gated channel Piezo2 is expressed in a subset of CA1 pyramidal neurons (Wang and Hamill, 2020). Piezo1 (Qiu et al, 2019) and TRP channels (Oh et al, 2020;Yoo et al, 2020) have been experimentally linked to ultrasound neuromodulation effects.…”

Intrinsic plasticity of cerebellar stellate cells is mediated by NMDA receptor regulation of voltage‐gated Na+ channels

“…For example, Piezo2 readily permeates Ca 2+ (Szczot et al . 2017) and is found in cerebellar neuronal somata (Wang & Hamill, 2020). Emerging channel subfamilies like NALCN and TACAN, which are activated and modulated by non‐traditional stimuli, like external Ca 2+ concentration (Chua et al .…”

“…Emerging channel subfamilies like NALCN and TACAN, which are activated and modulated by non-traditional stimuli, like external Ca 2+ concentration (Chua et al 2020) and high threshold mechanical stimulation (Beaulieu-Laroche et al 2020), respectively, might also play a role. These types of channels, studied mostly in the periphery, might serve uncharacterized purposes in the brain by acting like extracellular pressure sensors, much like some TRP channel isoforms in the hypothalamic osmoregulatory circuit (Ciura & Bourque, 2006;Sharif Naeini et al 2006), which are crucial in detecting changes to the extracellular space with blood flow (McBain et al 1990;Wang & Hamill, 2020). The fact that cerebellar SCs are so sensitive to external pressure/mechanical perturbation could be important to the synchronization of signal processing in J Physiol 599.2 the cerebellar cortex during vigorous activity, analogous to respiration-entrained oscillatory firing in the olfactory cortex and other brain regions (Zelano et al 2016;Herrero et al 2018;Piarulli et al 2018;Perl et al 2019).…”