Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses

Tanaka Mika, Shih Pei-Yu, Gomi Hiroshi, Yoshida Takamasa, Nakai Junichi, Ando Reiko, Furuichi Teiichi, Mikoshiba Katsuhiko, Semyanov Alexey, Itohara, Itohara Shigeyoshi

Description

Neuronal activity alters calcium ion (Ca 2+ ) dynamics in astrocytes, but the physiologic relevance of these changes is controversial. To examine this issue further, we generated an inducible transgenic mouse model in which the expression of an inositol 1,4,5-trisphosphate absorbent, “IP 3 sponge”, attenuates astrocytic Ca 2+ signaling. Results Attenuated Ca 2+ activity correlated with reduced astrocytic coverage of asymmetric synapses in the hippocampal CA1 region in these animals. The decreased astrocytic ‘protection’ of the synapses facilitated glutamate ‘spillover’, which was reflected by prolonged glutamate transporter currents in stratum radiatum astrocytes and enhanced N-methyl-D-aspartate receptor currents in CA1 pyramidal neurons in response to burst stimulation. These mice also exhibited behavioral impairments in spatial reference memory and remote contextual fear memory, in which hippocampal circuits are involved. Conclusions Our findings suggest that IP 3 -mediated astrocytic Ca 2+ signaling correlates with the formation of functional tripartite synapses in the hippocampus.

Sujets

• Astrocyte
• Calcium
• Synapse

Informations

• Publié par: biomed
• Publié le: 01 janvier 2013
• Nombre de lectures: 57
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Tanaka et al. Molecular Brain 2013, 6 :6 http://www.molecularbrain.com/content/6/1/6

R E S E A R C H Open Access Astrocytic Ca 2+ signals are required for the functional integrity of tripartite synapses Mika Tanaka 1 † , Pei-Yu Shih 1 † , Hiroshi Gomi 2 , Takamasa Yoshida 1 , Junichi Nakai 1,3 , Reiko Ando 1 , Teiichi Furuichi 1,5 , Katsuhiko Mikoshiba 1,4 , Alexey Semyanov 1* and Shigeyoshi Itohara 1*

Abstract Background: Neuronal activity alters calcium ion (Ca 2+ ) dynamics in astrocytes, but the physiologic relevance of these changes is controversial. To examine this issue further, we generated an inducible transgenic mouse model in which the expression of an inositol 1,4,5-trisphosphate absorbent, “ IP 3 sponge ” , attenuates astrocytic Ca 2+ signaling. Results: Attenuated Ca 2+ activity correlated with reduced astrocytic coverage of asymmetric synapses in the hippocampal CA1 region in these animals. The decreased astrocytic ‘ protection ’ of the synapses facilitated glutamate ‘ spillover ’ , which was reflected by prolonged glutamate transporter currents in stratum radiatum astrocytes and enhanced N-methyl-D-aspartate receptor currents in CA1 pyramidal neurons in response to burst stimulation. These mice also exhibited behavioral impairments in spatial reference memory and remote contextual fear memory, in which hippocampal circuits are involved. Conclusions: Our findings suggest that IP 3 -mediated astrocytic Ca 2+ signaling correlates with the formation of functional tripartite synapses in the hippocampus. Keywords: Astrocyte, Calcium, Synapse, Neuron-glia interaction

Background astrocytic IICR is attenuated, and examined the role of Astrocytes exhibit dynamic Ca 2+ mobilization via an inosi- astrocytic Ca 2+ signaling at the level of both the tripartite tol 1,4,5-trisphosphate (IP 3 )-induced Ca 2+ release (IICR)- synapse and behavior. dependent mechanism [1,2]. The role of astrocytic Ca 2+ dynamics, however, has been debated over the last decade Results [3]. Some studies report intact hippocampal short-and Attenuated agonist-evoked IICR in astrocytes by IP 3 long-term plasticity in situ in IP 3 receptor (IP 3 R)-type 2 buffering with a glutathione-S-transferase (GST)-IP 3 knockout mice, in which hippocampal astrocytes com- sponge pletely lack IICR [4,5], whereas others report that these  To investigate the in vivo role of Ca 2+ dynamics in astro- mice show no cholinergic-induced long-term potentiation  cytes, we generated two transgenic mouse lines (Figure 1A) (LTP) in vivo [6,7]. In situ evidence also indicates that hip-  in which IICR was attenuated by the expression of an IP 3 pocampal LTP depends on D-serine release from astro-  absorbent “ IP 3 sponge ” [13] in an astrocyte-specific and cytes under the control of astrocytic Ca 2+ signaling [8]. A  temporally controlled manner. In the Tg1:Tg2 double trans- number of reports describe spontaneous or stimulation-  genic (DTg) mice, lacZ reporter expression was efficiently evoked Ca 2+ activity in astrocytes in vivo [9-12], but still  induced in broad brain areas except for the cerebellum very little is known about the in vivo significance of astro-  (Figure 1, B and C). No gross histologic abnormalities were cytic Ca 2+ mobilization [6,7], especially in higher brain  observed in the brains of the DTg mice. Importantly, lacZ functions such as learning and memory. In the present  expression was detected in the majority of astrocytes in the study, we generated a new mouse model in which  DTg mouse hippocampus (Figure 1, D and E). Double immunolabeling revealed that lacZ induction was restricted * Correspondence: [e-mail] ; [e-mail] to the astrocytes (S100B-positive and NeuN-negative cells; 1 † R E I q K u E a N lc Br o a n i t n ri S b c u i t e o n r c s eInstitute,2-1Hirosawa,Wako351-0198,Japan Figure 1F and G, Additional file 1: Table S1). In several Full list of author information is available at the end of the article brain areas, including the hippocampal CA1 and dentate © 2013 Tanaka et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.