Genetic Inactivation of Two-Pore Channel 1 Impairs Spatial Learning and Memory
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ORIGINAL RESEARCH
Genetic Inactivation of Two-Pore Channel 1 Impairs Spatial Learning and Memory Robert Theodor Mallmann1 · Norbert Klugbauer1,2 Received: 6 April 2020 / Accepted: 28 July 2020 © The Author(s) 2020
Abstract Two-pore channels (TPCs) constitute a small family of cation channels that are localized in membranes of endosomal and lysosomal compartments. Although their roles for vesicular fusion and endolysosomal trafficking have been investigated, our knowledge on their expression pattern and higher order functions in the murine brain is still limited. Western blot analysis indicated a broad expression of TPC1 in the neocortex, cerebellum and hippocampus. In order to investigate the consequences of the genetic inactivation of TPC1, we performed a set of behavioural studies with TPC1−/− mice. TPC1−/− mice were analysed for an altered motor coordination and grip-strength, exploratory drive and anxiety as well as learning and memory. TPC1−/− mice did not show any differences in their exploratory drive or in their anxiety levels. There were also no differences in spontaneous activity or motor performance. However, the Morris water maze test uncovered a deficit in spatial learning and memory in TPC1−/− mice. Keywords Two-pore channel · TPC1 · NAADP · Morris water maze · Spatial learning
Introduction Two-pore channels (TPCs) constitute a small family of intracellularly localized cation channels. In mice and humans, only two TPCs have been identified, though, other species express three functional tpc-genes. Evolutionarily TPCs form intermediates between one-domain TRP and four-domain voltage gated N a+ or Ca2+ channels. TPCs are found in membranes of small and acidic intracellular organelles such as endosomes and lysosomes. Within these compartments, they show a smooth transition from TPC1 Edited by Jerry Stitzel. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10519-020-10011-1) contains supplementary material, which is available to authorized users. * Norbert Klugbauer [email protected]‑freiburg.de 1
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Albert-LudwigsUniversität, Freiburg, Germany
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany
2
predominantly found in early and recycling endosomes to TPC2 mainly expressed in late endosomes and lysosomes (reviewed in Galione et al. 2009, 2010; Patel 2015). Diversity of TPCs is even wider since the TPC1 gene is expressed not only as full-length isoform TPC1A, but also as an N-terminal truncated variant TPC1B (Ruas et al. 2014). Both isoforms demonstrate different co-localizations with markers of early and recycling endosomes and it is highly probable that the isoforms contribute to different endolysosomal functions. TPCs are assumed to be involved in the regulation of endocytic and recycling/degradation processes, such as vesicle tr
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