Postnatal expression of CD38 in astrocytes regulates synapse formation and adult social memory

• Published in: The EMBO journal 2023-08, Vol.42 (15), p.e111247-n/a
• Main Authors: Hattori, Tsuyoshi, Cherepanov, Stanislav M, Sakaga, Ryo, Roboon, Jureepon, Nguyen, Dinh Thi, Ishii, Hiroshi, Takarada‐Iemata, Mika, Nishiuchi, Takumi, Kannon, Takayuki, Hosomichi, Kazuyoshi, Tajima, Atsushi, Yamamoto, Yasuhiko, Okamoto, Hiroshi, Sugawara, Akira, Higashida, Haruhiro, Hori, Osamu
• Format: Article
• Language: English
• Subjects: Abnormalities; ADP-ribosyl Cyclase 1 - genetics; Adults; Animals; Antigens, CD - metabolism; astrocyte; Astrocytes; Astrocytes - metabolism; Brain; cADPR; Calcium; Calcium signalling; CD38 antigen; Circuits; Cyclic ADP-ribose; Cyclic ADP-Ribose - metabolism; EMBO27; Hippocampus; Hypothalamus; Life Sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Neurons; Oxytocin; Prefrontal cortex; Proteins; Ribose; Social behavior; Synapses; Synapses - metabolism; Synaptogenesis
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2022111247

Social behavior is essential for health, survival, and reproduction of animals; however, the role of astrocytes in social behavior remains largely unknown. The transmembrane protein CD38, which acts both as a receptor and ADP‐ribosyl cyclase to produce cyclic ADP–ribose (cADPR) regulates social behaviors by promoting oxytocin release from hypothalamic neurons. CD38 is also abundantly expressed in astrocytes in the postnatal brain and is important for astroglial development. Here, we demonstrate that the astroglial‐expressed CD38 plays an important role in social behavior during development. Selective deletion of CD38 in postnatal astrocytes, but not in adult astrocytes, impairs social memory without any other behavioral abnormalities. Morphological analysis shows that depletion of astroglial CD38 in the postnatal brain interferes with synapse formation in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, astroglial CD38 expression promotes synaptogenesis of excitatory neurons by increasing the level of extracellular SPARCL1 (also known as Hevin), a synaptogenic protein. The release of SPARCL1 from astrocytes is regulated by CD38/cADPR/calcium signaling. These data demonstrate a novel developmental role of astrocytes in neural circuit formation and regulation of social behavior in adults. Synopsis Postnatal expression of the ADP‐ribosyl cyclase CD38 in astrocytes regulates neuronal circuit formation and social behavior in adults. Postnatal expression, but not adult expression, of CD38 in astrocytes regulates social memory. Astrocytic CD38 promotes excitatory synapse formation in the medial prefrontal cortex and hippocampal CA1 and CA2. Astrocytic CD38 promotes secretion of the synaptogenic protein SPARCL1 via cyclic ADP–ribose and calcium signaling. Graphical Abstract Astrocytes regulate neuronal development and social behavior via the transmembrane protein and ADP‐ribosyl cyclase CD38.