4.2 Functional implications of CB1R in PV-interneurons
Although CB1Rs are present in many different cell types in the brain, the specific function of CB1Rs is largely determined by the cell type and subcellular compartment in which they are expressed. Indeed, our findings highlight an important role of cell type specific CB1Rs in hearing. In the current study, our results demonstrated that the conditional deletion of the Cnr1 gene from PV interneurons resulted in a decrease in both the number of cells expressing CB1Rs and the protein expression levels of CB1Rs, and also lead to hearing loss at 32 kHz and auditory dysfunction, as revealed by the ABR test. The transgenic mice with CB1Rs deficiency in PV-interneurons exhibited the prolongation of waves I latencies, suggesting that auditory nerve-brainstem conduction velocity is decreased. Furthermore, a decrease in the amplitudes of waves I-V observed in the transgenic mice with CB1Rs deficiency suggesting an abnormal auditory brainstem function.
The SOC plays a critical role in azimuthal sound localization, particularly in processing interaural level differences (ILD) and interaural time differences (ITD), which are essential for determining the direction of sound sources in space (Tzounopoulos and Kraus, 2009). In Cnr1-cKO mice, the significant decrease in CB1R-positive neurons and CB1Rs expression within the SOC, accompanied by drastic changes in wave II and wave III of the ABR, suggests that the CB1Rs signaling in SOC plays a crucial role in the normal functioning of auditory pathways. Therefore, the sculpting of CB1Rs expression patterns across the central auditory system would provide crucial insights into the role of CB1Rs as a neuromodulator in auditory function. The differential expression of CB1Rs in various auditory regions, especially in inhibitory interneurons like PV-positive GABAergic neurons, highlights the significant role these receptors play in regulating auditory processing, synaptic plasticity, and sound localization. Although the expression of CB1Rs in the MGB and AC was relatively low in comparison to regions like the CN, SOC and LL, the roles of CB1Rs in these auditory nuclei still warrant further exploration.
Beyond the physiological function of CB1Rs, our findings may provide insight into the biological mechanisms of the auditory dysfunction such as tinnitus (Y et al., 2015; Hwang and Chan, 2016; Pf and Y, 2016; Ji et al., 2017; Zugaib and Leão, 2018; Y and Pf, 2019). A study by Jason et al. (2011) highlighted a significant link between decreased GABAergic inhibition and hyperactivity in the DCN, which is proposed as a mechanism underlying tinnitus following noise exposure (Middleton et al., 2011). Recent studies have increasingly pointed to dysfunctional GABAergic inhibition, particularly involving PV interneurons, as a key factor in the generation or perception of tinnitus (36,48). Specifically, the changes in CB1Rs expression and the number of CB1R-positive neurons in the CN in salicylate-induced tinnitus models provide a compelling link between CB1Rs dysfunction and tinnitus (Zheng et al., 2007). The use of cannabinoid compounds, particularly tetrahydrocannabinol (THC) and cannabidiol (CBD), for the treatment of tinnitus has indeed garnered growing attention in clinical research (46,47). Therefore, the identification of CB1Rs distribution patterns across the central auditory system, coupled with an understanding of their physiological roles in GABAergic inhibitory interneurons, is crucial for unraveling the mechanisms behind auditory dysfunctions like hearing loss and tinnitus.
In summary, our findings highlight the critical role of CB1Rs in regulating PV+ GABAergic interneuron circuits within the central auditory system. The selective deletion of CB1Rs in these cells disrupts inhibitory function, leading to hearing loss at 32 kHz and abnormal auditory brainstem responses. These results underscore the importance of CB1Rs signaling in maintaining proper auditory processing and suggest that CB1Rs dysfunction in GABAergic interneurons could contribute to auditory pathologies such as tinnitus and hearing deficits. Our study provides valuable insights into how endocannabinoid signaling, particularly through CB1Rs, influences auditory processing at the level of specific cell populations within the auditory system.