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

Area of Science:

• Neuroscience
• Neuroimmunology
• Molecular Biology

Background:

• The P2Y12 receptor (P2Y12R) is primarily expressed in microglia within the central nervous system.
• Microglial P2Y12R plays a role in neurological conditions such as chronic pain, stroke, and seizures.
• The specific function of microglial P2Y12R in controlling neuronal excitability and innate behaviors remains unclear.

Purpose of the Study:

• To investigate the role of microglial P2Y12R in regulating neuronal excitability and innate fear behaviors.
• To determine if P2Y12R deletion affects fear responses in developing and adult mice.

Main Methods:

• Generation of constitutive and inducible P2Y12R knockout mouse models using P2Y12-floxed mice crossed with CX3CR1-Cre or CX3CR1-CreER lines.
• Comprehensive behavioral testing battery to assess innate and learned fear behaviors.
• Electrophysiological recordings (whole-cell patch clamp) and c-fos expression analysis in hippocampal neurons.

Main Results:

• Both constitutive and induced P2Y12R knockout mice displayed innate fear behaviors but not learned fear behaviors.
• Elevated c-fos expression was observed in the ventral hippocampus CA1 neurons of P2Y12R knockout mice after elevated plus maze exposure.
• Increased excitability of ventral hippocampus CA1 neurons was confirmed in P2Y12R knockout mice via patch clamp recordings.

Conclusions:

• Microglial P2Y12R is a key regulator of neuronal excitability in the ventral hippocampus.
• Deletion of microglial P2Y12R significantly impacts innate fear behaviors in both developing and adult mice.
• These findings highlight the critical role of microglial P2Y12R in modulating neural circuits underlying fear and behavior.