Studio multidisciplinare di un modello genetico della Sclerosi Laterale Amiotrofica (SLA).

Aim of the present activity is to realize a computer model of the neuron encompassing all the most recent findings about this cell’s functioning, as integrated by the novel acquisitions that will eventually emerge during the present project. The present activity will be devoted to develop and to validate a mathematical model of neuronal cell incorporating all processes known participating in the definition of ion dynamics across cell’s membrane and in the cytoskeleton(?). Both passive spread (diffusion through either non-gated or gated ionic channels following concentration gradients) and active transport mechanisms (movement against electrochemical gradient forced by pumps using energy from the hydrolysis of ATP) will be included in the model. The whole membrane current will be expressed as the sum of several ionic currents. Each of the current will be modeled by functions of transmembrane potential and intra- and extra-cellular ionic concentrations. Many of the currents will also include time-dependent gating variables whose opening and closing kinetic rates are functions of transmemrane potential or of the concentration of neurotransmitters. In analyzing diffusive currents through non-gated channels, we will characterize the contributions to them by the fluxes of the main different ions Na+, K+, Ca2+ and Cl-. As for currents flowing through gated channels, we will distinguish between currents flowing through voltage-gated channels (whose conductance will be variable with memebrane potential), proton-gated channels (which will activate sensitive to pH), ligand-gated channels (whose conductance will be affected by binding to neurotransmitters), and second messenger-gated channels (which will require two-step activation, first by transmitter binding and secondary via phosphorylation). More detailed, we will separately consider voltage-gated currents of sodium (fast inactivating INa(fast) and non- or slow inactivating INa(slow)), potassium (Delayed-Rectifier IK(DR), transient A IK(A), slowly inactivating Delay current IK(D), subthreshold non-inactivating Muscarine-sensitive IK(M), fast Ca2+-gated IK(Ca), After-HyperPolarization IK(AHP), fast Inward Rectifier IK(IR)), calcium (high-threshold Long-lasting ICa(L), low-threshold Transient ICa(T), high-threshold Neither L nor T ICa(N), high threshold Purkinje cell-type ICa(P)), cloride (time-dependent ICl, Ca2+-gated ICl(Ca)) and non-ion specific leak currents. We will also separaterly study ligand-gated kainate- , AMPA- and kainate+GYKI-induced currents (ionotropic KAinate receptor channels’ IKA and ionotropic AMPA receptor channels’ IAMPA). As for currents substained by proton pumps, we will characterize the action of the Na+-Ca2+ exchanger and that of the Na+-K+ exchanger.