The Role of TRPA1 Channels in the Central Processing of Odours Contributing to the Behavioural Responses of Mice

Abstract

Transient receptor potential ankyrin 1 (TRPA1), a nonselective cation channel, contributes to several (patho)physiological processes. Smell loss is an early sign in several neurodegenerative disorders, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases; therefore, we focused on its role in olfaction and social behaviour with the aim to reveal its potential therapeutic use. The presence of Trpa1 mRNA was studied along the olfactory tract of mice by combined RNAscope in situ hybridisation and immunohistochemistry. The aversive effects of fox and cat odour were examined in parallel with stress hormone levels. In vitro calcium imaging was applied to test if these substances can directly activate TRPA1 receptors. The role of TRPA1 in social behaviour was investigated by comparing Trpa1 wild-type and knockout mice (KO). Trpa1 mRNA was detected in the olfactory bulb and piriform cortex, while its expression was weak in the olfactory epithelium. Fox, but not cat odour directly activated TRPA1 channels in TRPA1-overexpressing Chinese Hamster Ovary cell lines. Accordingly, KO animals showed less aversion against fox, but not cat odour. The social interest of KO mice was reduced during social habituation–dishabituation and social interaction, but not during resident–intruder tests. TRPA1 may contribute to odour processing at several points of the olfactory tract and may play an important role in shaping the social behaviour of mice. Thus, TRPA1 may influence the development of certain social disorders, serving as a potential drug target in the future.

Transient receptor potential ankyrin 1 ion channel expressed by the Edinger-Westphal nucleus contributes to stress adaptation in murine model of posttraumatic stress disorder

“…Limited knowledge is available about its location and role in the central nervous system. Its expression has already been confirmed by our research group in certain stress-related brain areas, including olfactory bulb, piriform cortex (Konkoly et al, 2021), hypothalamus (Olah et al, 2021) and dorsal raphe nucleus (DR) (Milicic et al, unpublished). The highest level of Trpa1 mRNA expression was found in the urocortinergic neurons of the centrally projecting Edinger-Westphal nucleus (EWcp) in mice (Kormos et al, 2022).…”

“…The RNAscope ISH was performed on two different series of coronal EWcp sections to detect the Ucn1 and Trpa1 mRNA expression. RNAscope Multiplex Fluorescent Reagent Kit v.2 (Advanced Cell Diagnostics, Newark, CA, United States ) was used according to the protocol described earlier by our research group ( Konkoly et al, 2021 ). Briefly, after the tissue pretreatment, samples were hybridized with the probe specific to mouse Trpa1 (ACD, Cat.…”

Peptidergic neurons of the Edinger–Westphal nucleus express TRPA1 ion channel that is downregulated both upon chronic variable mild stress in male mice and in humans who died by suicide

“…Further experiments using pharmacological tools and electrophysiological recordings are needed to determine how TRPA1 signalling contributes to maladaptation via UCN1 neurons. Given the relatively restricted and low expression of TRPA1 in the brain, 60,61 we propose that its pharmacological modulation will act mainly on the EWcp, with valuable therapeutic significance and limited side effects in the central nervous system.…”

“…Possible developmental compensations may have contributed to the behavioural phenotype of our global knockout mouse strain. Because the functional receptor was deleted both in the periphery and in some brain areas where limited 60,61 neuronal Trpa1 expression is also found, we could not exclude the possibility that other peripheral or central mechanisms that we did not examine here may have contributed to the behavioural phenotype of knockout mice. Because no reliable TRPA1 receptor antibody is available, we are unable to present protein-level data.…”

Temporal Appearance of Enhanced Innate Anxiety in Alzheimer Model Mice

“…Using Ni-DAB immunohistochemistry, we were able to confirm the progressive appearance of the classical hallmark of AD (Aβ and pTau) in brain areas important for memory formation (e.g., hippocampus; Figure 6F,G and Figure 7A-D) as well as in the amygdala, an important center of emotions including anxiety (Figure 6H,I and Figure 7E,F). Moreover, the deposits were detectable in the OB (Figure 6A-C) and piriform cortex (Figure 7E,F), brain areas participating in olfaction [29]. Interestingly, Aβ was only minimally present in two-month-old animals, while the signal intensity for pTau was already high in this age group.…”