Spontaneous waves of electrical activity propagate across many structures of the central nervous system during critical stages of early development. It is now known that specialized pacemaker neurons are responsible for initiating these waves, but it is not clear how such pacemakers operate, or what properties determine some neurons to initiate the waves and other neurons to propagate the waves once they are initiated. A great deal of attention has been paid to how the synaptic interactions between neurons serve to initiate and propagate spontaneous waves. Very little is known, however, about how these immature neurons transform their synaptic inputs to spike train outputs, and how this computation is involved in wave initiation and propagation. Recent collaborative experiments of our two laboratories have used white noise current stimuli delivered to single neurons in the developing mouse cortex to try to understand how these neurons extract features from their synaptic inputs and compute their outputs. This work has shown that near the end of the first postnatal week, cortical neurons acquire the ability to scale their output function to the amplitude of their inputs, thus reducing the gain between input amplitude and spike frequency output. At late embryonic and early postnatal stages, however, many cortical neurons lack this gain scaling ability. These early stages correspond to those at which spontaneous waves of activity are generated in the cortex. Recent experiments in one of our laboratories have shown that cortical waves are driven by a pacemaker population in the ventrolateral quadrant of the cortex. We propose here to test the hypothesis that the pacemaker neurons in this region are the neurons that show the most pronounced lack of gain scaling, and that this inability to scale output to input amplitude effectively is one of the properties required for their pacemaking function. High-speed calcium imaging will be used to identify the location of the pacemaker in individual slices, and then whole-cell recordings and white noise stimuli will be applied to neurons in that region to measure their gain scaling ability. This will be compared to neurons in follower regions to see whether lack of gain scaling correlates with pacemaker function. These data will be combined with recordings of synaptic inputs in the pacemaker neurons to create neuronal models to test whether the inability to scale spike train outputs to synaptic input amplitudes is the computational property that determines pacemaker function.
Waves of electrical activity cross the brain during early development and are essential for the correct wiring of brain circuitry. The present experiments study how the properties of single neurons cause them to trigger this activity. The work will provide insights into defects in brain development that occur in humans, and in particular how abnormal electrical activity, such as seizures, can disrupt brain development.
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