Pcdhβ deficiency affects hippocampal CA1 ensemble activity and contextual fear discrimination - PubMed (original) (raw)

doi: 10.1186/s13041-020-0547-z.

Noriaki Ohkawa 1 2 3, Yoshito Saitoh 1 2 3, Khaled Ghandour 1 2, Emi Murayama 1 2, Hirofumi Nishizono 4, Mina Matsuo 4, Teruyoshi Hirayama 5, Ryosuke Kaneko 6, Shin-Ichi Muramatsu 7 8, Takeshi Yagi 9, Kaoru Inokuchi 10 11

Affiliations

Pcdhβ deficiency affects hippocampal CA1 ensemble activity and contextual fear discrimination

Hirotaka Asai et al. Mol Brain. 2020.

Abstract

Clustered protocadherins (Pcdhs), a large group of adhesion molecules, are important for axonal projections and dendritic spread, but little is known about how they influence neuronal activity. The Pcdhβ cluster is strongly expressed in the hippocampus, and in vivo Ca2+ imaging in Pcdhβ-deficient mice revealed altered activity of neuronal ensembles but not of individual cells in this region in freely moving animals. Specifically, Pcdhβ deficiency increased the number of large-size neuronal ensembles and the proportion of cells shared between ensembles. Furthermore, Pcdhβ-deficient mice exhibited reduced repetitive neuronal population activity during exploration of a novel context and were less able to discriminate contexts in a contextual fear conditioning paradigm. These results suggest that one function of Pcdhβs is to modulate neural ensemble activity in the hippocampus to promote context discrimination.

Keywords: CA1; Ca2+ imaging; Clustered protocadherin; Contextual fear memory; Discrimination; Ensemble; Hippocampus; Pcdhβ.

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Conflict of interest statement

SM owns equity in a company (Gene Therapy Research Institution) that commercializes the use of AAV vectors for gene therapy applications. To the extent that the work in this manuscript increases the value of these commercial holdings, SM has a conflict of interest. The other authors declare that they have no competing interests.

Figures

Fig. 1

Fig. 1

Pcdhβ deficiency reduces repetitive neuronal activity in the hippocampus. a Pcdhβ deletion. b Induction of CaMKII-G-CaMP7 by AAV and implantation of GRIN lens over the right hippocampal CA1 region. c Ca2+ imaging in home cage (pre) and square context (sq). d Schematic of the correlation matrix analysis. Representative images of correlation matrices for activation in Wt (e) and Δβ (f) mice. g Summation of correlation coefficients between sessions (n = 5 Wt mice, 4 Δβ mice). Data are means ± standard errors of the means (SEMs). **P < 0.01 (adjusted _P_-value from Bonferroni’s multiple-comparison test)

Fig. 2

Fig. 2

Pcdhβ deficiency affects ensemble size and the proportion of neurons shared between ensembles. Representative images of binarized basis matrices from Wt (a) and Δβ (b) mice. Yellow dots represent the cells contributing to the ensemble. c–d Normalized number of ensembles according to ensemble size. Statistical values from Bonferroni’s multiple-comparison test are provided in Additional file 6: Table S1 (n = 5 Wt mice, 4 Δβ mice). Data are means ± SEMs. **P < 0.01 (adjusted _P_-value from Bonferroni’s multiple-comparison test). Percentages of neuronal cells contributing to one ensemble (open bars) and multiple ensembles (pattern and solid bars) in Wt and Δβ mice during pre (e) and sq (f) sessions. ****P < 0.0001 (chi-square test)

Fig. 3

Fig. 3

Pcdhβ deficiency impairs context discrimination. a Schematic image of contextual fear conditioning task. b Freezing levels in test sessions. Square: F(21, 18) = 2.140, P = 0.1080; _t_39 = 1.141, P = 0. 2607; circle: F(18, 21) = 1.153, P = 0.7479; _t_39 = 1.301, P = 0.2008; unpaired _t_-test. c Discrimination indices of both contexts. F(18, 21) = 1.645, P = 0.2737; _t_39 = 2.310, P = 0.0263; unpaired _t_-test. (n = 19 Wt mice, 22 Δβ mice). Data are means ± SEMs

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