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.