An innovative mouse model to understand the role of ATP receptor P2X4 in Brain diseases as well as in peripheral disorders.
The ATP receptor protein P2X4 is overexpressed on the surface of different cell types in numerous brain disorders as well as in peripheral disorders, its implication of this surface remained elusive. To understand its function in the various pathological contexts, the researchers created a mouse model in which surface P2X4 receptors are increased in specific cell types thereby mimicking distinct pathological conditions. This study, published in the journal Molecular Psychiatry, validates the strategy and demonstrates that increased surface levels of P2X4 in certain neurons of the transgenic mice alters cellular processes involved in memory and learning, resulting in decreased levels of anxiety and memory deficits.
The ATP receptor P2X4 is expressed in many cell types throughout the body, most notably in neurons and glial cells of the brain. This protein, which is expressed at low levels under normal conditions, is overexpressed by certain neurons and /or glial cells in neurodegenerative diseases such as Alzheimer’s disease, Amyotrophic lateral sclerosis , multiple sclerosis, chronic pain and other pathologies like those related to alcohol consumption. Additionally, increased surface P2X4 levels are observed in cells of the periphery during pathology, such as inflammation, asthma or rheumatoid arthritis suggesting that the P2X4 receptor could be a key player in many pathologies and therefore a promising therapeutic target. In order to understand P2X4 receptor functions, Eric Boué-Grabot’s lab, at the institute of Neurodegenerative diseases (IMN) of Bordeaux, developed with the Strasbourg Mouse Clinic a transgenic knock-in mouse model which allows the increase P2X4 receptors on the surface of certain cells. The results published in the journal Molecular Psychiatry, obtained in collaboration with several French, European and Canadian teams demonstrate that increased levels of P2X4 on the surface of forebrain neurons involved in learning and memory lead to memory deficits and reduced anxiety-like behaviors in knock-in mice. These studies suggest that the increase in P2X4 receptors on the surface of neurons, as observed in Alzheimer’s disease may contribute to memory deficits and more generally may have key role in various neuropsychiatric disorders.
This study furthermore underscores the potential of this new transgenic mouse model in which P2X4mCherryIN fluorescence represents a unique tool to directly monitor increased P2X4 expression in pathological models. These knock-in mice are an important tool to elucidate the role of P2X4 in different pathologies including brain, lung and heart disorders.
Figure: P2X4 receptor (in green) is almost absent at the surface of hippocampal neurons (in magenta) of control mice (top left) but greatly increased at the surface of the same neurons in P2X4mCherryIN mice expressing the modified form of the P2X4 receptor (green, top right). Image at the bottom shows the enlargement of a neuronal extension (dendrite), where P2X4mCherryIN receptors are detected intracellular (in red) and on the dendritic surface (in green). Some clusters of surface P2X4mCherryIN receptors are located close to the areas of communication between neurons (synapses, in blue). © Eric Boué-Grabot / CNRS
For more information:
Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice. Bertin E*, Deluc T*, Pilch KS*, Audrey Martinez A, Pougnet JT, Doudnikoff E, Allain AE, Bergmann P, Russeau M, Toulmé E, Bezard E, Koch-Nolte F, Séguéla P, Lévi S, Bontempi B, Georges F, Bertrand SS, Nicole O and Boué-Grabot E. (*co-first authors)
Molecular Psychiatry DOI : 10.1038/s41380-019-0641-8
On publication, the article will be available at the following link:
https://www.nature.com/articles/s41380-019-0641-8
Contact:
Dr Eric Boué-Grabot
Research Director CNRS à l’Institut des Maladies Neurodégénératives (IMN)
CNRS / université de Bordeaux
Bordeaux Neurocampus
eric.boue-grabot@u-bordeaux.fr