Activation of the hippocampal CA1 astrocyte Gq and Gi G protein-coupled receptors exerts a protective effect against attention deficit hyperactivity disorder

Abstract

Background

Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms such as inattention, hyperactivity and impulsiveness, which significantly impact the healthy development of children. Our prior research demonstrated that exposure to S-Ketamine during pregnancy can lead to the development of ADHD, and existing studies have established a close association between astrocytes and the onset and progression of ADHD. The activation and inhibition of astrocytes are closely linked to neuropsychiatric dysfunction, and astrocytic NOD-like receptor protein 3 (NLRP3) has been reported to contribute to alterations in mental state and cognitive deficits. Thus, this study aims to investigate the role of astrocytes in ADHD by selectively modulating astrocyte function through Gq and Gi G protein-coupled receptors (GPCRs) and by specifically targeting the knockout of NLRP3.

Methods

Pregnant C57BL/6 J mice or mice with a specific deletion of NLRP3 in astrocytes were administered intraperitoneal injections of 15 mg/kg of S-ketamine for 5 consecutive days from gestational day 14 to 18 to establish an ADHD model. To modulate astrocyte activity in the hippocampal CA1 region, we administered astrocyte-specific Gq-Adeno-associated virus (AAV) or Gi-AAV into the CA1 and maintained treatment with CNO. At 21 days postnatally, we conducted open field test (OFT), novel object recognition (NOR), elevated plus maze (EPM) and fear conditioning (FC) in the offspring mice. Additionally, on postnatal day 21, we implanted electrodes in the CA1 region of the offspring mice for neurophysiological monitoring and investigated local field potentials (LFP) during NOR on postnatal day 27. Lastly, pathological assessments were conducted after euthanasia.

Results

Both the activation and inhibition of astrocytes in the hippocampal CA1 region improved impulsive-like behaviors and cognitive function in ADHD mice, reduced the power of theta (θ) oscillations during novel object exploration and decreased NLRP3-associated inflammatory factors, including cleaved caspase-1 and IL-18. Furthermore, compared to WT mice, astrocyte-specific NLRP3 conditional knockout mice demonstrated significantly reduced impulsive behavior and cognitive deficits, as well as a decrease in θ oscillation power and a reduction in NLRP3-associated inflammatory factors.

Conclusions

Our data provide compelling evidence that the activation of astrocytes alleviated impulsive-like behaviors and cognitive dysfunction, possibly by reducing NLRP3-associated pyroptosis following changes in calcium levels within the astrocytes. The activation of astrocytes can be a potential therapeutic target for ADHD.