Research

Hippocampus-dependent memory loss in Alzheimer' Disease. 

Our research on Alzheimer's disease (AD) focuses on beta-amyloid (Aβ)-induced antagonistic effects on selective nicotinic acetylcholine receptor (nAChR) subtypes in hippocampal activity at the cellular and network levels and memory processes. Given that cholinergic deficiency is associated with AD, strategies aiming to restore normal cholinergic functions have been developed as therapeutic drugs for AD, including several acetylcholinesterase inhibitors. Unfortunately, restoring normal cholinergic activity by increasing overall acetylcholine levels has only been moderately successful, potentially due to unforeseen adverse effects from non-selective stimulation of acetylcholine receptors. Our new idea that co-activation of selective nAChRs (Roberts et al., 2021 and Sun et al., 2019) is required to reverse the detrimental effects of Aβ on memory in AD will provide innovative and novel pharmaceutical methods. 

Autism-related social dysfunction. 

Another line of our research deals with the role of δ-catenin in social behavior. Genetic alterations in the δ-catenin gene in humans are associated with severely affected autism spectrum disorder (ASD) patients from multiple families. However, the links between δ-catenin and social behavior are largely unknown. δ-catenin is important for the localization and function of glutamatergic AMPA receptors (AMPARs) at excitatory synapses in many brain regions (Farooq et al., 2016). We will address how δ-catenin regulates postsynaptic glutamatergic activity in prefrontal neurons to adjust mPFC neuronal activity and their network computations in the control of social behavior. In fact, our preliminary data show that δ-catenin knockout (KO) and ASD-associated δ-catenin missense mutant mice exhibit social dysfunction with in vivo and in vitro glutamatergic dysfunction. However, it is still unknown how δ-catenin regulates glutamatergic activity in the mPFC and social behavior. Our study is thus critical for a better understanding of the mechanisms that contributes to social behavior. To examine our hypothesis, we will employ two new mouse models of loss of δ-catenin functions: δ-catenin KO mice and human ASD-associated δ-catenin missense mutant mice (Mendez-Vazquez H et al., 2023). 

Ketamine and depression. 

After demonstrating rapid and robust antidepressant efficacy, the US Food and Drug Administration (FDA) approved ketamine in 2019, sparking a surge in clinical and public interest around the world. Ketamine enhances excitatory synaptic drive in the hippocampus, which is presumed to underlie its rapid antidepressant. However, it remains unknown how ketamine rapidly enhances excitatory synaptic transmission in the hippocampus to induce its rapid antidepressant effects. We will fill this gap by discovering the molecular, cellular, and synaptic underpinnings of the pro-cognitive effects of ketamine. We have strong preliminary data demonstrating that ketamine rapidly induces the expression of unique Ca2+-Permeable, GluA2-lacking, and GluA1-containing AMPA receptors (CP-AMPARs) to prevent depression-like behavior in mice. Our previous works on AMPARs (Sathler et al., 2021 and Shou et al., 2018) and new findings lead us to hypothesize that ketamine rapidly promotes the expression of CP-AMPARs, in turn enhances synaptic strength in the hippocampus to induce antidepressant effects (Zaytseva A et al., 2023).