Itzhak Mano

Normal and abnormal signaling by glutamate, the main excitatory neurotransmitter in the brain, forms the basis for fundamental paradigms such as learning and memory, maladaptive behaviors such as drug addiction-associated reinforcement, and psychiatric conditions such as major depressive disorder and schizophrenia. The study of molecular signaling events in the nervous system has benefited tremendously from a reductionist approach, using simple animals as genetically accessible model systems. Further to this approach, we study glutamatergic signaling in the nematode C. elegans. While some basic paradigms (such as associative learning and dopamine-mediated indulgence on food) are reproducible in these animals, the obvious differences between complex and simple animals drive us to focus our research on the study of the basic cellular events in normal and pathological glutamatergic signaling. We are focusing on two critical aspects: 1) Mechanisms of glutamate clearance that prevent synaptic accumulation and spillover between synapses, to ensure the fidelity of signaling and the separation of neuronal circuits. 2) Mechanisms of neurodegeneration following excessive stimulation of glutamatergic synapses, similar to the damage seen in the mammalian brain following cerebral ischemia. Molecular and cellular mechanisms in neuronal signaling are astonishingly well conserved from nematodes to humans. We therefore hope that by using the power of molecular genetic analysis in C. elegans we might provide novel insights that could be used as guidance to study glutamatergic signaling processes in the nervous system of higher animals, and its involvement in normal behavior and psychiatric disorders.