Inhibition sculpts neural activity through various cell types and circuits, but, unlike excitation, it is not self-propagating and must be locally recruited with a temporal delay. Here the authors show a fast, feedforward inhibitory mechanism that bypasses synaptic delay through ephaptic coupling of an interneuron to the axon initial segment of a projection cell.
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Amphibian and mammalian rods can both detect single photons of light even though they differ greatly in physical dimensions, mammalian rods being much smaller in diameter than amphibian rods. To understand the changes in physiology and biochemistry required by such large differences in outer segment geometry, we developed a computational approach, taking into account the spatial organization of the outer segment divided into compartments, together with molecular dynamics simulations of the signaling cascade. We generated simulations of the single-photon response together with intrinsic background fluctuations in toad and mouse rods. Combining this computational approach with electrophysiological data from mouse rods, we determined key biochemical parameters. On average around one phosphodiesterase (PDE) molecule is spontaneously active per mouse compartment, similar to the value for toad, which is unexpected due to the much smaller diameter in mouse. A larger number of spontaneously active PDEs decreases dark noise, thereby improving detection of single photons ; it also increases cGMP turnover, which accelerates the decay of the light response. These constraints explain the higher PDE density in mammalian compared with amphibian rods that compensates for the much smaller diameter of mammalian disks. We further find that the rate of cGMP hydrolysis by light-activated PDE is diffusion limited, which is not the case for spontaneously activated PDE. As a consequence, in the small outer segment of a mouse rod only a few activated PDEs are sufficient to generate a signal that overcomes noise, which permits a shorter lifetime of activated rhodopsin and greater temporal resolution.
The constant dynamic movement of synapses and their components has emerged in the last decades as a key feature of synaptic transmission and its plasticity. Intramolecular protein movements drive conformation changes important to transduce transmitter binding into signaling. Constant cytoskeletal rearrangements power synapse shape movements. Vesicular trafficking at the pre- and postsynapse underlies transmitter release and receptor traffic between the cell surface and intracellular compartments, respectively. Receptor movement in the plane of the plasma membrane by thermally powered Brownian diffusion movement and reversible trapping by receptor-scaffold interactions has emerged as the main mechanism to dynamically organize the synaptic membrane in nanoscale domains. We will discuss here the different conceptual and methodological advances that have led to a rethinking of the synapse as an organelle whose function is tightly linked to its dynamic organization.