The molecular basis for electrogenic computation in the brain: you can't step in the same river twice

Abstract

Neural computation has classically been considered to be a process that depends, in large part, on the integration of excitatory and inhibitory synaptic signals by postsynaptic neurons; these cells generate sequences of action potentials that convey their messages, in turn, to still other neurons. We now appreciate that synaptic activity is a dynamic process that can be altered by mechanisms that include sprouting, pruning, facilitation, potentiation, and depression. But what about the electrogenic properties of neurons, ie the capability of these cells to generate all-or-non action potentials? Recent work indicates that the electrogenic machinery within neurons is also dynamic as a result of plasticity in the expression of sodium channels within the neuronal membrane. Molecular and functional remodeling of electrogenic membrane has been most extensively studied in developing and diseased neurons, but also occurs in the normal brain. The molecular plasticity of electrogenic membrane has important functional implications, since it can retune the neuron, changing its input-output relations.Keywords: sodium channels; action potential electrogenesis; neural coding; information processing; CNS plasticityThe ten billion neurons within the brain and spinal cord form a computer that is more complex and flexible than any device produced thus far by man. According to the classical Sherringtonian model, each neuron integrates incoming information so as to generate a sequence of regenerative action potentials that conveys its message to other neurons. Information processing in the central nervous system, according to this model, involves the generation of complex patterns of action potentials by neurons which integrate the activity at excitatory and inhibitory synapses which impinge upon them. Synaptic mechanisms underlying these excitatory and inhibitory effects have been studied in detail-indeed, we now understand not only the steady-state behavior of synapses, but also appreciate that synaptic activity is a dynamic process that can be altered by mechanisms that include sprouting, pruning, facilitation, potentiation and depression.Since electrogenicity, ie, the capability of neurons to generate action potentials, contributes substantially to their integrative function, an understanding of its molecular basis may provide insights into the molecular underpinnings of higher function. The seminal work of Hodgkin and Huxley demonstrated that, in most neurons, voltage-gated sodium channels are responsible for the regenerative depolarization that underlies the Correspondence: SG Waxman, MD, PhD, Department of Neurology, LCI 707,