P2X4 receptor functions in the CNS revealed using P2X4 internalization-defective knock-in mice
Institute for Neurodegenerative Diseases [IMN] (Bordeaux, France)
P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons and/or glia. P2X receptors has profound neuromodulatory effects on synaptic efficacy and plasticity at both the excitatory and inhibitory synapses. The surface trafficking of P2X4 receptors is highly regulated and as a result, P2X4 are mainly intracellular, limiting their putative implication in ATP signaling originating from either neuron or glia in normal conditions. This is likely to be important because an upregulation of surface P2X4 receptors in neurons and/or glia was observed in various pathophysiological context such as ischemia, chronic pain, epilepsy, multiple sclerosis or neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) or Alzheimer disease (AD). To elucidate functions of P2X4, we created a conditional P2X4 internalization-defective knock-in mice (P2X4KI) to increase the number of P2X4 receptors at the surface of the targeted cells. In the first part of my talk, I will present the validation of two P2X4KI models and how increased neuronal P2X4 contribute to synaptic deficits in the hippocampus and alterations in anxiety and memory functions. In the second part, I will talk about the roles of P2X4 receptors in ALS pathogenesis in SOD1-G93A mice revealed using P2X4KO or P2X4KI mice and how misfolded mutant SOD1 proteins increase surface expression of P2X4.
Currently we are hosting our seminar in Zoom. The link is available to external people on request.