Microglial P2Y12 receptor regulates ventral hippocampal CA1 neuronal excitability and innate fear in mice

Jiyun Peng,Long-Jun Wu,Anthony D Umpierre,Yong Liu,Dai-Shi Tian,Manling Xie,Jason R Richardson

doi:10.1186/s13041-019-0492-x

Abstract

The P2Y12 receptor (P2Y12R) is a purinoceptor that is selectively expressed in microglia in the central nervous system. As a signature receptor, microglial P2Y12R mediates process chemotaxis towards ADP/ATP gradients and is engaged in several neurological diseases including chronic pain, stroke and seizures. However, the role of microglial P2Y12R in regulating neuronal excitability and innate behaviors is not fully understood. Here, we generated P2Y12-floxed mice to delete microglial P2Y12R beginning in development (CX3CR1Cre/+:P2Y12f/f; “constitutive knockout”), or after normal development in adult mice (CX3CR1CreER/+:P2Y12f/f; “induced knockout”). Using a battery of behavioral tests, we found that both constitutive and induced P2Y12R knockout mice exhibited innate fear but not learned fear behaviors. After mice were exposed to the elevated plus maze, the c-fos expression in ventral hippocampus CA1 neurons was robustly increased in P2Y12R knockout mice compared with wild-type mice. Consistently, using whole cell patch clamp recording, we found the excitability of ventral hippocampus CA1 neurons was increased in the P2Y12R knockout mice. The results suggest that microglial P2Y12R regulates neuronal excitability and innate fear behaviors in developing and adult mice.

Highlights

Microglia are the resident immune cells in the central nervous system (CNS) and play key roles in health and disease [1,2,3,4,5]
TREM2 and DAP12 are selectively expressed in CNS microglia and their mutations were linked to Nasu-Hakola disease (NHD), a condition that results in dementia [9,10,11]
To investigate how microglial P2Y12 receptor (P2Y12R) deficiency alters the neuronal circuits for innate fear behaviors, we examined the c-fos expression in Ventral hippocampus (vHPC) and medial pre-frontal cortex (mPFC) at 45 min after the mice were exposed to elevated plus maze (EPM) (10 min trial)

Summary

Introduction

Microglia are the resident immune cells in the central nervous system (CNS) and play key roles in health and disease [1,2,3,4,5]. Microglia have been reported to be important for brain development, circuit formation, via pruning excessive synapses as well as inducing spine formation [6,7,8]. TREM2 and DAP12 are selectively expressed in CNS microglia and their mutations were linked to Nasu-Hakola disease (NHD), a condition that results in dementia [9,10,11]. The unique feature of microglia is that they have dynamic processes that survey the brain parenchyma constantly [21, 22].

Methods

Results

Conclusion