Fusogen-mediated neuron−neuron fusion disrupts neural circuit connectivity and alters animal behavior

Significance Ramón y Cajal’s neuron doctrine, which states that neurons are individual cells that do not share any membrane or cytoplasmic continuity between them, has underpinned our view of modern neuroscience. However, there is considerable evidence that fusogens, specialized proteins essential and sufficient for the fusion of cells in other tissues, are expressed in the nervous system of several species in response to viral infection, stress conditions, and neurological disease. By manipulating the expression of fusogens in the chemosensory neurons of Caenorhabditis elegans, our results provide conclusive evidence that deregulation of fusogen expression causes neuronal fusion and can have deleterious effects on neural circuitry and behavioral outputs, revealing a possible novel underlying cause of neurological disorders. The 100-y-old neuron doctrine from Ramón y Cajal states that neurons are individual cells, rejecting the process of cell−cell fusion in the normal development and function of the nervous system. However, fusogens—specialized molecules essential and sufficient for the fusion of cells—are expressed in the nervous system of different species under conditions of viral infection, stress, or disease. Despite these findings, whether the expression of fusogens in neurons leads to cell−cell fusion, and, if so, whether this affects neuronal fate, function, and animal behavior, has not been explored. Here, using Caenorhabditis elegans chemosensory neurons as a model system, we provide proof-of-principle that aberrant expression of fusogens in neurons results in neuron−neuron fusion and behavioral impairments. We demonstrate that fusion between chemoattractive neurons does not affect the response to odorants, whereas fusion between chemoattractive and chemorepulsive neurons compromises chemosensation. Moreover, we provide evidence that fused neurons are viable and retain their original specific neuronal fate markers. Finally, analysis of calcium transients reveals that fused neurons become electrically coupled, thereby compromising neural circuit connectivity. Thus, we propose that aberrant expression of fusogens in the nervous system disrupts neuronal individuality, which, in turn, leads to a change in neural circuit connectivity and disruption of normal behavior. Our results expose a previously uncharacterized basis of circuit malfunction, and a possible underlying cause of neurological diseases.