Binggui Sun'group published in PNAS on new mechanisms underlying the excitability of CA2 pyramidal neurons and social recognition
Social behaviors such as social interaction, recognition and memory are critical for daily life of animals including human beings, and social deficits including social withdraw, anxiety and isolation are closely associated with psychological or neurological disorders1. Therefore, it is important to elucidate the mechanisms of social behaviors.
It has been well known that anterior cingulate cortex (ACC) is a social hub in the brain2, and recent studies demonstrate that hippocampal CA2 pyramidal neurons (PNs) play important roles in social recognition memory3. Binggui Sun’s laboratory in Zhejiang University School of Brain Science and Brain Medicine published a paper in PNAS entitled “Efr3b is essential in social recognition by regulating the excitability of CA2 pyramidal neurons”, providing new insights into the association of CA2 PNs and social behaviors.
Efr3 (Eighty-five requiring 3) is the mammalian and yeast homologue of the drosophila rolling blackout (RBO). Previous studies have shown that RBO/Efr3 is important in terms of the phospholipid metabolism at the plasma membrane4. Efr3 includes Efr3a and Efr3b in mammalian cells. Although both Efr3a and Efr3b are highly expressed in the brain, their physiological functions in the brain are largely unknown. We reported previously that deficiency of Efr3a led to increased expression of BDNF and it’s receptor, TrkB5. In the present study, our data of RNAscope in situ hybridization showed that the mRNA of Efr3b was widely expressed in the brain and highly enriched in the hippocampal CA2/CA3 areas. We crossed Nestin-cre mice with Efr3bf/f mice to specifically delete Efr3b in neural cells. Behavioral tests revealed that deficiency of Efr3b in neural cells resulted in impaired social novelty recognition but did not affect the spatial learning and memory, anxiety, fear memory, social interaction and olfactory functions of mice. These phenotypes are very similar with the behaviors of mice after specific inhibition of CA2 PNs reported in a previous study3. Our electrophysiological recordings also showed that the excitability of CA2 PNs was significantly reduced in mice of Efr3b deficiency, suggesting that ablating Efr3b may affect the excitability of CA2 PNs and then impairs the ability of social novelty recognition of mice.
To further assess the functions of Efr3b, we specifically knocked down the expression of Efr3b in CA2 PNs via RNAi. We found that reducing Efr3b in CA2 PNs decreased the excitability of CA2 PNs and impaired the social novelty recognition of mice. Interestingly, restoring the expression of Efr3b in CA2 PNs increased their excitability and improved the ability of social novelty recognition in Efr3b-deficient mice. Furthermore, chemogenetic activation of CA2 PNs also improved the social novelty recognition of Efr3b-deficient mice. Collectively, these data indicate that Efr3b is essential in social recognition by maintaining the excitability of CA2 PNs, and deficiency or dysfunction of Efr3b may account for relevant disorders associated with social deficits.
Dr. Binggui Sun of Zhejiang University School of Brain Science and Brain Medicine is the leading corresponding author and Drs. Fude Huang and Xuekun Li are co-corresponding authors. Drs. Xiaojie Wei and Jing Wang are the co-first authors of this paper. Yiping Zhang, Enlu Yang and Qi Qian in Binggui Sun’s lab also contribute to this study. This work was supported by grants from National Key Research and Development Program of China (2021YFA1101701, 2019YFA0110103), National Natural Science Foundation of China (31871025, 32071031, 32271028), Natural Science Foundation of Zhejiang Province (LZ19C090001), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2023-PT310-01).
References
1. Kennedy DP, Adolphs R. The social brain in psychiatric and neurological disorders. Trends Cogn. Sci. 2012, 16: 559-572.
2. Apps MA, et al. The anterior cingulate gyrus and social cognition: tracking the motivation of others. Neuron 2016, 90: 692-707.
3. Hitti FL, Siegelbaum SA. The hippocampal CA2 region is essential for social memory. Nature 2014, 508: 88-92.
4. Baird D, et al. Assembly of the PtdIns 4-kinase Stt4 complex at the plasma membrane requires Ypp1 and Efr3. J Cell Biol 2008, 183: 1061-1074.
5. Qian Q, et al. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway. FASEB J 2017, 31:2104-2113.
