4.1 The wide distribution of CB1Rs across the central auditory system
The ECS and its components have been the subject of extensive research, particularly for their roles in synaptic plasticity and neurodevelopment (Tzounopoulos et al., 2007; Clarke et al., 2021). While much has been studied about the ECS and its components, particularly CB1Rs, in various regions of the CNS, much less attention has been given to how CB1Rs are distributed and function in the central auditory system. Cnr1 transcripts that encode CB1Rs have been detected in various brain regions using RNA scope or in situ hybridization, however, the actual expression characteristics of CB1Rs proteins themselves-especially in the central auditory system-remain an underexplored area (Erben and Buonanno, 2019; Tao et al., 2020).
In the current study, we systematically evaluated the differentiated expression patterns of CB1Rs in the central auditory system using immunostaining. Immunostaining is an excellent way to complement in situ hybridization of mRNA transcripts, and allows for direct visualization of CB1Rs proteins in specific neuronal populations and subcellular compartments, providing valuable insights into how CB1Rs are distributed across various auditory nuclei. Our findings demonstrated that the expression of CB1Rs in the CN, SOC, IC, LL, MGB, and AC of mice are in line with previous studies, further supporting the idea that CB1Rs are widely distributed across regions of the central auditory system (Zheng et al., 2007; Zhao et al., 2011; Ji et al., 2017). Specifically, the observation that CB1Rs are particularly abundantly enriched in the CN, SOC suggest that CB1Rs play a role in modulating early auditory processing.
We also found that CB1Rs are highly expressed in PV interneurons across several auditory nuclei. The functions of CB1Rs are not solely determined by their expression levels in specific neuronal subpopulations but are also closely related to the downstream efficacy of their G protein-dependent signaling and cell-type specific signaling dynamics. For instance, in the hippocampus, where GABAergic neurons express much higher levels of CB1Rs than glutamatergic neurons, the fact that the G protein-dependent signaling of CB1Rs is less effective in GABAergic neurons suggests that CB1Rs function can be modulated by contextual factors beyond mere receptor density (Steindel et al., 2013). Likewise, the capacity of CB1Rs to modulate neurotransmission and synaptic plasticity is indeed influenced not only by their expression levels in specific cell types but also by the distinct functional properties of these cells (Huang and Paul, 2019).