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IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours.

Yasumura M, Yoshida T, Yamazaki M, Abe M, Natsume R, Kanno K, Uemura T, Takao K, Sakimura K, Kikusui T, Miyakawa T, Mishina M - Sci Rep (2014)

Bottom Line: Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice.Furthermore, the behavioural flexibility was slightly reduced in the T-maze test.These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Liaison Academy, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.

ABSTRACT
IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.

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Decreased spine density in IL1RAPL1 knockout mice.(A) Western blot analysis of the immunoprecipitates of whole brain lysates from wild-type (Il1rapl1+/Y) and IL1RAPL1 knockout (Il1rapl1−/Y) mice with anti-IL1RAPL1 antiserum. (B) Nissl-stained parasagittal whole brain sections of Il1rapl1+/Y and Il1rapl1−/Y mice. (C) Nissl-stained sections of hippocampus and cerebral cortex of Il1rapl1+/Y and Il1rapl1−/Y mice. (D) Accumulation of Shank2 signals of cultured cortical neurons from Il1rapl1+/Y and Il1rapl1−/Y mice by beads conjugated with PTPδ-ECD-Fc or Fc protein. (E) Intensity of staining signals for Shank2 on the surface of beads conjugated with PTPδ-ECD-Fc or Fc protein (n = 11–12). (F) Decrease in spine density of basal dendrites of hippocampal CA1 and cortical layer 2/3 pyramidal neurons in IL1RAPL1 knockout mice. (G) Spine densities of basal dendrites of hippocampal CA1 and cortical layer 2/3 pyramidal neurons of wild-type (n = 47 and 43 neurons, respectively from 3 animals) and IL1RAPL1 knockout (n = 31 and 29 neurons, respectively from 2 animals) mice. All values represent mean ± SEM. * P < 0.05, ** P < 0.01 and *** P < 0.001, respectively; Tukey's test (E) or t-test (G). Scale bars represent 5 mm in (B), 1 mm in (C) and 5 μm in (D, F).
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f1: Decreased spine density in IL1RAPL1 knockout mice.(A) Western blot analysis of the immunoprecipitates of whole brain lysates from wild-type (Il1rapl1+/Y) and IL1RAPL1 knockout (Il1rapl1−/Y) mice with anti-IL1RAPL1 antiserum. (B) Nissl-stained parasagittal whole brain sections of Il1rapl1+/Y and Il1rapl1−/Y mice. (C) Nissl-stained sections of hippocampus and cerebral cortex of Il1rapl1+/Y and Il1rapl1−/Y mice. (D) Accumulation of Shank2 signals of cultured cortical neurons from Il1rapl1+/Y and Il1rapl1−/Y mice by beads conjugated with PTPδ-ECD-Fc or Fc protein. (E) Intensity of staining signals for Shank2 on the surface of beads conjugated with PTPδ-ECD-Fc or Fc protein (n = 11–12). (F) Decrease in spine density of basal dendrites of hippocampal CA1 and cortical layer 2/3 pyramidal neurons in IL1RAPL1 knockout mice. (G) Spine densities of basal dendrites of hippocampal CA1 and cortical layer 2/3 pyramidal neurons of wild-type (n = 47 and 43 neurons, respectively from 3 animals) and IL1RAPL1 knockout (n = 31 and 29 neurons, respectively from 2 animals) mice. All values represent mean ± SEM. * P < 0.05, ** P < 0.01 and *** P < 0.001, respectively; Tukey's test (E) or t-test (G). Scale bars represent 5 mm in (B), 1 mm in (C) and 5 μm in (D, F).

Mentions: We generated IL1RAPL1 knockout mice using C57BL/6 embryonic stem cells24 (see Supplementary Fig. S1 online). The IL1RAPL1 knockout mice grew and mated normally. Western blot analysis confirmed the absence of IL1RAPL1 of ~85 kDa in the brain of the mutant mice (Fig. 1A). The size and proportion of the brain and the Nissl-staining patterns of the cerebral cortex and hippocampus of the mutant mice were comparable to those of the wild-type mice in agreement with a previous report25 (Fig. 1B and C).


IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours.

Yasumura M, Yoshida T, Yamazaki M, Abe M, Natsume R, Kanno K, Uemura T, Takao K, Sakimura K, Kikusui T, Miyakawa T, Mishina M - Sci Rep (2014)

Decreased spine density in IL1RAPL1 knockout mice.(A) Western blot analysis of the immunoprecipitates of whole brain lysates from wild-type (Il1rapl1+/Y) and IL1RAPL1 knockout (Il1rapl1−/Y) mice with anti-IL1RAPL1 antiserum. (B) Nissl-stained parasagittal whole brain sections of Il1rapl1+/Y and Il1rapl1−/Y mice. (C) Nissl-stained sections of hippocampus and cerebral cortex of Il1rapl1+/Y and Il1rapl1−/Y mice. (D) Accumulation of Shank2 signals of cultured cortical neurons from Il1rapl1+/Y and Il1rapl1−/Y mice by beads conjugated with PTPδ-ECD-Fc or Fc protein. (E) Intensity of staining signals for Shank2 on the surface of beads conjugated with PTPδ-ECD-Fc or Fc protein (n = 11–12). (F) Decrease in spine density of basal dendrites of hippocampal CA1 and cortical layer 2/3 pyramidal neurons in IL1RAPL1 knockout mice. (G) Spine densities of basal dendrites of hippocampal CA1 and cortical layer 2/3 pyramidal neurons of wild-type (n = 47 and 43 neurons, respectively from 3 animals) and IL1RAPL1 knockout (n = 31 and 29 neurons, respectively from 2 animals) mice. All values represent mean ± SEM. * P < 0.05, ** P < 0.01 and *** P < 0.001, respectively; Tukey's test (E) or t-test (G). Scale bars represent 5 mm in (B), 1 mm in (C) and 5 μm in (D, F).
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f1: Decreased spine density in IL1RAPL1 knockout mice.(A) Western blot analysis of the immunoprecipitates of whole brain lysates from wild-type (Il1rapl1+/Y) and IL1RAPL1 knockout (Il1rapl1−/Y) mice with anti-IL1RAPL1 antiserum. (B) Nissl-stained parasagittal whole brain sections of Il1rapl1+/Y and Il1rapl1−/Y mice. (C) Nissl-stained sections of hippocampus and cerebral cortex of Il1rapl1+/Y and Il1rapl1−/Y mice. (D) Accumulation of Shank2 signals of cultured cortical neurons from Il1rapl1+/Y and Il1rapl1−/Y mice by beads conjugated with PTPδ-ECD-Fc or Fc protein. (E) Intensity of staining signals for Shank2 on the surface of beads conjugated with PTPδ-ECD-Fc or Fc protein (n = 11–12). (F) Decrease in spine density of basal dendrites of hippocampal CA1 and cortical layer 2/3 pyramidal neurons in IL1RAPL1 knockout mice. (G) Spine densities of basal dendrites of hippocampal CA1 and cortical layer 2/3 pyramidal neurons of wild-type (n = 47 and 43 neurons, respectively from 3 animals) and IL1RAPL1 knockout (n = 31 and 29 neurons, respectively from 2 animals) mice. All values represent mean ± SEM. * P < 0.05, ** P < 0.01 and *** P < 0.001, respectively; Tukey's test (E) or t-test (G). Scale bars represent 5 mm in (B), 1 mm in (C) and 5 μm in (D, F).
Mentions: We generated IL1RAPL1 knockout mice using C57BL/6 embryonic stem cells24 (see Supplementary Fig. S1 online). The IL1RAPL1 knockout mice grew and mated normally. Western blot analysis confirmed the absence of IL1RAPL1 of ~85 kDa in the brain of the mutant mice (Fig. 1A). The size and proportion of the brain and the Nissl-staining patterns of the cerebral cortex and hippocampus of the mutant mice were comparable to those of the wild-type mice in agreement with a previous report25 (Fig. 1B and C).

Bottom Line: Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice.Furthermore, the behavioural flexibility was slightly reduced in the T-maze test.These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Liaison Academy, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.

ABSTRACT
IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.

Show MeSH
Related in: MedlinePlus