Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes

  1. Nicoletta Galeotti1,3,
  2. Alessandro Quattrone2,
  3. Elisa Vivoli1,
  4. Monica Norcini1,
  5. Alessandro Bartolini1, and
  6. Carla Ghelardini1
  1. 1 Department of Preclinical and Clinical Pharmacology, University of Florence, I-50139 Florence, Italy;
  2. 2 Laboratory of Magnetic Resonance Center and FiorGen Foundation, University of Florence, 50019 Florence, Italy

Abstract

The administration of the ryanodine receptor (RyR) agonist 4-Cmc (0.003–9 nmol per mouse intracerebroventricularly [i.c.v.]) ameliorated memory functions, whereas the RyR antagonist ryanodine (0.0001–1 nmol per mouse i.c.v.) induced amnesia in the mouse passive avoidance test. The role of the type 1, 2, and 3 RyR isoforms in memory processes was then evaluated by inhibiting the expression of the three RyR proteins in the mouse brain. A selective knockdown of the RyR isoforms was obtained by the i.c.v. administration of antisense oligonucleotides (aODNs) complementary to the sequence of RyR1, RyR2 and RyR3 proteins, as demonstrated by immunoblotting experiments. RyR1 (5–9 nmol per mouse i.c.v.) knockdown mice did not show any memory dysfunction. Conversely, RyR2 (1–7 nmol per mouse i.c.v.) and RyR3 (1–7 nmol per mouse i.c.v.) knockdown animals showed an impairment of memory processes. This detrimental effect was temporary and reversible, disappearing 7 d after the end of the aODN treatment. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous mobility and inspection activity, as revealed by the hole-board test. In conclusion, the lack of any involvement of cerebral RyR1 was demonstrated. These findings also showed the involvement of type 2 and type 3 RyR in the modulation of memory functions identifying these cerebral RyR isoforms as critical targets underlying memory processes.

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