TRPC channels are not required for graded persistent activity in entorhinal cortex neurons

Abstract

Adaptive behavior requires the transient storage of information beyond the physical presence of external stimuli. This short‐lasting form of memory involves sustained (“persistent”) neuronal firing which may be generated by cell‐autonomous biophysical properties of neurons or/and neural circuit dynamics. A number of studies from brain slices reports intrinsically generated persistent firing in cortical excitatory neurons following suprathreshold depolarization by intracellular current injection. In layer V (LV) neurons of the medial entorhinal cortex (mEC) persistent firing depends on the activation of cholinergic muscarinic receptors and is mediated by a calcium‐activated nonselective cation current (ICAN). The molecular identity of this conductance remains, however, unknown. Recently, it has been suggested that the underlying ion channels belong to the canonical transient receptor potential (TRPC) channel family and include heterotetramers of TRPC1/5, TRPC1/4, and/or TRPC1/4/5 channels. While this suggestion was based on pharmacological experiments and on effects of TRP‐interacting peptides, an unambiguous proof based on TRPC channel‐depleted animals is pending. Here, we used two different lines of TRPC channel knockout mice, either lacking TRPC1‐, TRPC4‐, and TRPC5‐containing channels or lacking all seven members of the TRPC family. We report unchanged persistent activity in mEC LV neurons in these animals, ruling out that muscarinic‐dependent persistent activity depends on TRPC channels.

Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells

“…While it remains unclear what alternative mechanism than TRPC could support persistent firing in TRPC KO mice (e.g., TRPC hepta-KO), channels such as TRPM4 and 5 [90], and hERG [62] might be some of the possible mechanisms. It is also interesting to point out that Egorov and colleagues (2019) observed neurons which did not support persistent firing only in the TRPC hepta-KO group [59], where compensation of the mechanisms supporting persistent firing might be more challenging due to the deletion of all TRPC family members, compared to the TRPC1,4,5 triple-KO.…”

“…As mentioned above, recent studies in TRPC knockout mice may contradict the role for TRPC discussed above [58,59]. Dasari and colleagues (2013) used TRPC1, TRPC5, TRPC6, and TRPC5 and 6 double KO mice, and demonstrated that plateau potentials measured in the medial prefrontal cortex under a cholinergic activation were intact [58].…”

“…While plateau depolarization was suppressed in TRPC4 and TRPC7 KO mice [56,57], Dasari and colleagues (2013) have shown that plateau depolarization was not altered in the medial prefrontal cortex of TRPC1, TRPC5, TRPC6 and TRPC5,6 double KO mice [58]. Egorov and colleagues (2019) have more recently shown that persistent firing in TRPC1,4,5 triple-KO and TRPC1-7 hepta-KO was intact in the entorhinal cortex [59]. Interestingly, however, behavioral studies have shown that TRPC 1,4,5 triple KO mice [60] and TRPC1 KO mice [61] are impaired in working memory tasks, which is very much in line with the idea that TRPC dependent persistent firing supports working memory.…”

Transient Receptor Potential Canonical (TRPC) Channels: Then and Now

“…Notably, there are neural activities that do not depend on TRPCs. Egorov et al used triple-KO mouse line lacking TRPC1, TRPC4, and TRPC5 and hepta-KO mouse line lacking all seven TRPC channels (TRPC1-7) and found that graded persistent activity did not depend on TRPC channels in entorhinal cortex neurons [ 227 ].…”

RNA-seq analysis reveals TRPC genes to impact an unexpected number of metabolic and regulatory pathways

“…As a consequence of the complex scenario found in the field of TRPC research, we developed mice that lack all of the TRPC channels (TRPC hepta knockout mice) that have been experimentally characterized (see refs. 17,18 ). The aim of this work was to address the impact of the absence of all TRPC channels on gene expression in several tissues simultaneously and ask at a global level which functions depend on TRPC channels during their normal functioning.…”