Biology subjects

Guan, A.

Publications and source records attributed to Guan, A..

3 recordsLinked to original sources

bioRxiv2026

Dual Roles of Interferon-γ Receptor in Somatostatin Interneurons at Baseline and During Inflammation

Background: Neuropsychiatric disorders such as major depressive disorder show converging evidence of gamma-aminobutyric acid (GABA) dysfunction, including consistent reductions in somatostatin (SST) interneuron markers. SST interneurons are selectively vulnerable to inflammation, yet the underlying mechanisms remain unclear. Interferon-gamma (IFN-{gamma}), a pro-inflammatory cytokine implicated in mood and anxiety disorders, signals through the IFN-{gamma} receptor (IFNGR), which is expressed in neurons. We tested whether IFNGR signaling in SST interneurons regulates anxiety-like and cognitive behavior and prevents inflammation-induced molecular deficits. Methods: We generated mice with conditional deletion of IFNGR from SST cells and assessed anxiety-like behavior using elevated plus maze and working memory using Y-maze at baseline and after lipopolysaccharide (LPS) induced inflammation. Expression of SST-related, neurotrophic, synaptic, and glial markers was quantified. Results: At baseline and after LPS-induced inflammation, IFNGR deletion in SST cells increased anxiety-like behavior without affecting working memory. In control mice, LPS reduced Sst (p=0.0006), neuropeptide Y (Npy) (p=0.0022), brain-derived neurotrophic factor (Bdnf) (p<0.0001), and synapsin 1 (Syn1) (p=0.0150); these reductions were not significant in mice lacking IFNGR in SST cells. Knockouts also showed lower baseline Bdnf, Syn1, Gephyrin (Gphn), and allograft inflammatory factor 1 (Aif1, encoding Iba1) than controls. Conclusions: IFNGR signaling in SST cells plays a dual role: supporting normal behavior and molecular homeostasis while mediating LPS-induced molecular deficits. These findings link immune signaling to the GABAergic dysfunction implicated in major depressive disorder and suggest IFNGR signaling in SST cells may regulate cortical microcircuit integrity at baseline and during inflammatory challenge.

neuroscience↗

bioRxiv2019

Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinsons disease

Human genetic variants causing loss-of-function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinsons disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns5-8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9 and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

genomics↗

bioRxiv2017

Distributed Rhythm Generators Underlie Caenorhabditis elegans Forward Locomotion

Coordinated rhythmic movements are ubiquitous in animal behavior. In many organisms, chains of neural oscillators underlie the generation of these rhythms. In C. elegans, locomotor wave generation has been poorly understood; in particular, it is unclear where in the circuit rhythms are generated, and whether there exists more than one such generator. We used optogenetic and ablation experiments to probe the nature of rhythm generation in the locomotor circuit. We found that multiple sections of forward locomotor circuitry are capable of independently generating rhythms. By perturbing different components of the motor circuit, we localize the source of secondary rhythms to cholinergic motor neurons in the midbody. Using rhythmic optogenetic perturbation we demonstrate bidirectional entrainment of oscillations between different body regions. These results show that, as in many other vertebrates and invertebrates, the C. elegans motor circuit contains multiple oscillators that coordinate activity to generate behavior.

neuroscience↗