Ping-jing Cai

Bio: Ping-jing Cai is an academic researcher from South China Normal University. The author has contributed to research in topics: GABAB receptor & Striatum. The author has co-authored 1 publications.

Gene Expression Analysis of the Endocannabinoid System in Presymptomatic APP/PS1 Mice

Abstract: Alzheimer’s disease (AD) is the most common type of dementia and neurodegeneration. The actual cause of AD progression is still unknown and no curative treatment is available. Recently, findings in human samples and animal models pointed to the endocannabinoid system (ECS) as a promising therapeutic approach against AD. However, the specific mechanisms by which cannabinoid drugs induce potential beneficial effects are still undefined. For this reason, it is required a full characterization of the ECS at different time points of AD progression considering important factors such as sex or the analysis of different brain regions to improve future cannabinoid-dependent therapies in AD. Thus, the main aim of the present study is to expand our knowledge of the status of the ECS in a presymptomatic period (3 months of age) using the AD mouse model APP/PS1 mice. First, we evaluated different behavioral domains including anxiety, cognitive functions, and social interactions in male and female APP/PS1 mice at 4 months of age. Although a mild working memory impairment was observed in male APP/PS1 mice, in most of the behaviors assessed we found no differences between genotypes. At 3 months of age, we performed a characterization of the ECS in different brain regions of the APP/PS1 mice considering the sex variable. We assessed the expression of the ECS components by quantitative Real-Time Polymerase Chain Reaction in the hippocampus, prefrontal cortex, hypothalamus, olfactory bulb, and cerebellum. Interestingly, gene expression levels of the type-1 and type-2 cannabinoid receptors and the anabolic and catabolic enzymes, differed depending on the brain region and the sex analyzed. For example, CB1R expression levels decreased in both hippocampus and prefrontal cortex of male APP/PS1 mice but increased in female mice. In contrast, CB2R expression was decreased in females, whereas males tended to have higher levels. Overall, our data indicated that the ECS is already altered in APP/PS1 mice at the presymptomatic stage, suggesting that it could be an early event contributing to the pathophysiology of AD or being a potential predictive biomarker.

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum

Abstract: Although the deubiquitinase cylindromatosis (CYLD), an abundant protein in the postsynaptic density fraction, plays a crucial role in mediating the synaptic activity of the striatum, the precise molecular mechanism remains largely unclear. Here, using a Cyld-knockout mouse model, we demonstrate that CYLD regulates dorsolateral striatum (DLS) neuronal morphology, firing activity, excitatory synaptic transmission, and plasticity of striatal medium spiny neurons via, likely, interaction with glutamate receptor 1 (GluA1) and glutamate receptor 2 (GluA2), two key subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). CYLD deficiency reduces levels of GluA1 and GluA2 surface protein and increases K63-linked ubiquitination, resulting in functional impairments both in AMPAR-mediated excitatory postsynaptic currents and in AMPAR-dependent long-term depression. The results demonstrate a functional association of CYLD with AMPAR activity, which strengthens our understanding of the role of CYLD in striatal neuronal activity.

Amyloid-β Protein Precursor Regulates Electrophysiological Properties in the Hippocampus via Altered Kv1.4 Expression and Function in Mice.

Abstract: BACKGROUND Amyloid-β protein precursor (AβPP) is enriched in neurons. However, the mechanism underlying AβPP regulation of neuronal activity is poorly understood. Potassium channels are critically involved in neuronal excitability. In hippocampus, A-type potassium channels are highly expressed and involved in determining neuronal spiking. OBJECTIVE We explored hippocampal local field potential (LFP) and spiking in the presence and absence of AβPP, and the potential involvement of an A-type potassium channel. METHODS We used in vivo extracellular recording and whole-cell patch-clamp recording to determine neuronal activity, current density of A-type potassium currents, and western blot to detect changes in related protein levels. RESULTS Abnormal LFP was observed in AβPP-/- mice, including reduced beta and gamma power, and increased epsilon and ripple power. The firing rate of glutamatergic neurons reduced significantly, in line with an increased action potential rheobase. Given that A-type potassium channels regulate neuronal firing, we measured the protein levels and function of two major A-type potassium channels and found that the post-transcriptional level of Kv1.4, but not Kv4.2, was significantly increased in the AβPP-/- mice. This resulted in a marked increase in the peak time of A-type transient outward potassium currents in both glutamatergic and gamma-aminobutyric acid-ergic (GABAergic) neurons. Furthermore, a mechanistic experiment using human embryonic kidney 293 (HEK293) cells revealed that the AβPP deficiency-induced increase in Kv1.4 may not involve protein-protein interaction between AβPP and Kv1.4. CONCLUSION This study suggests that AβPP modulates neuronal firing and oscillatory activity in the hippocampus, and Kv1.4 may be involved in mediating the modulation.