Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice

Contribution of P2X4 Receptors to CNS Function and Pathophysiology

“…Altogether, these findings strongly suggest that abnormal trafficking and proteolytic processing of the P2X4 protein may contribute to neuronal cell death in neurodegenerative diseases. This idea is further supported by data obtained using a conditional knock-in mice (P2X4mCherryIN) mimicking the pathological increase of surface P2X4 [59]. The increased expression of P2X4R at the surface of excitatory neurons decreases anxiety, impairs memory processing and alters activity-dependent synaptic plasticity phenomena in the hippocampus suggesting that upregulation of neuronal P2X4 observed in AD [71] may have key roles in AD pathogenesis [59].…”

“…The pathological implications of P2X4 endocytosis blockage has been recently analyzed using a new genetic tool, conditional transgenic knock-in P2X4 mice (Floxed P2X4mCherryIN), allowing the Cre activity-dependent genetic swapping of the internalization motif of P2X4 by the fluorescent mCherry protein to prevent constitutive endocytosis of P2X4 [59]. These mice overexpress P2X4R at the surface of the targeted cells, mimicking the pathological increased surface P2X4 + state.…”

“…In section, we review data supporting the role of P2X4 in the etiology of CNS disorders and the rationale for therapies based on P2X4 receptor modulation (see summary in Table 1). P2X4 −/− mice lack mechanical hyperalgesia and have reduced inflammatory pain [40,51] Neuropathic pain was alleviated in the present of P2X4 antagonists such as paroxetine, duloxetine, NP-1815-PX [64,65] Spinal cord and peripheral nerve injury Spinal cord injury in mice P2X4R −/− mice showed impaired inflammasome signaling and improved functional outcome [45] Sciatic nerve crush in mice Overexpression of P2X4R promoted motor and sensory functional recovery [50] Epilepsy Kainate induced status epilepticus in mice P2X4 −/− mice showed ameliorated microglia response and reduced neuronal death [66] Ischemia Middle cerebral artery occlusion (MCAO) (60 min) in mice P2X4 −/− mice showed reduced infarct volume [67] MCAO in mice P2X4R antagonists did not affect MCAO-mediated infarct formation [68] Neonatal hypoxia in mice TNP-ATP antagonist reduced hypomyelination and cognitive decline [69] Multiple sclerosis Experimental autoimmune encephalomyelitis Ivermectin ameliorate clinical signs [24] Lysolecithin (LPC) model in organotypic slices Ivermectin potentiates remyelination after in LPC-induced demyelination [24] Parkinson's disease 6-hydroxydopamine model of DA depletion P2X4R KO mice exhibited an attenuated levodopa (L-DOPA)-induced motor behavior, whereas ivermectin enhanced this behavior [70] Alzheimer's disease Amyloid β (Aβ) exposure in vitro Overexpression of P2X4Rs in neurons enhanced Aβ toxicity while silencing of P2X4Rs decreased neuronal death [71] Conditional knock-in mice (P2X4mCherryIN) mimicking the pathological increase of surface P2X4R Impairment of memory processing and altered synaptic plasticity in the hippocampus [59] Psychiatric disorders P2X4R KO mice P2X4 KO mice showed altered prepulse inhibition and reductions in social interactions [70,72,73] Alcohol use disorders models in mice Ivermectin and other avermectins reduces EtOH intake and preference [74,75] Anxiety Increases surface expression of P2X4 at excitatory synapses alleviates anxiety [59]…”

Cross-Talk between P2X and NMDA Receptors

“…Until recently, the modulatory nature of P2Xs (including regulation of NMDARs) was inextricably linked to their ability to permeate calcium. However, with the characterization of a novel knock-in mouse strain, where P2X4 is fluorescently labeled and internalization-deficient (P2X4mCherryIn), a more nuanced role for P2X has emerged [ 15 ]. The study demonstrated that in CA1 synapses, P2X4mCherryIn mice displayed no changes in basal excitatory transmission, but exhibit changes to LTP and LTD induction.…”

“…Roles for P2X4 in behavior have continued to emerge; studies have found that P2X4 KO mice: (1) show cognitive-behavioral deficits, (2) consume significantly more ethanol as compared to wildtype controls and (3) display aberrant signaling within the mesolimbic pathway of the brain [ 9 , 10 , 11 ]. Moreover, pharmacologic and genetic studies support the significance of P2X4 in cognitive function (for a detailed review on P2X modulators in disease, see [ 12 ]); P2X4 positive allosteric modulators (e.g., ivermectin and moxidectin) have been shown to reduce ethanol intake in wildtype, [ 13 , 14 ] and internalization-deficient P2X4 knock-in mice, which display increased surface expression of P2X4, demonstrate that P2X4 regulates anxiety and memory processes [ 15 ]. Indeed, increased P2X4 surface expression in excitatory neurons was shown to alter long-term depression and long-term potentiation (LTD and LTP) in the hippocampus, consistent with the idea that post-synaptic P2X4 receptors may regulate NMDAR function.…”