Zheng, K.; (2009) Rapid diffusion in the brain extracellular space - biophysical constraints and physiological implications. Doctoral thesis , UCL (University College London).

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Abstract

Physiological experiments backed by biophysical models have shown that, in central glutamatergic synapses, changes in extracellular diffusivity or glutamate transporter functions exert significant influences on the excitatory transmission. Failures of transporter functions have also been related to neurological disorders. The underlying biophysical mechanisms remain poorly understood. Here, we first combine two‐photon excitation imaging with electrophysiology to estimate the diffusivity of small soluble molecules, such as glutamate in the hippocampal neuropil (area CA1). Next, we adopt time‐resolved fluorescence anisotropy imaging microscopy to establish the previously unknown instantaneous diffusivity of small molecules in the extracellular space. The result indicates that nanometer‐scale diffusivity in the brain extracellular space is 25‐30% slower than that in free medium. Accounting for this retardation may have fundamental consequences for accurate interpretation of diffusion‐limited reactions in the brain. To obtain insight into the mechanisms contributing to the excitatory signal formation, we incorporate these results in a newly developed Monte‐Carlo model of the typical environment of small excitatory synapses including unevenly distributed receptors and transporters. In addition, we build a macroscopic three‐dimensional compartmental model of the hippocampal neuropil based on available experimental data to examine the effect of transporter distribution on the extracellular landscape of glutamate. Monte‐Carlo simulations show to what extent altering diffusivity inside or outside the synaptic cleft affect synaptic responses. Modelling also predicts that extrasynaptic transporters have little effect on fast synaptic transmission through AMPARs and NMDARs. However, they influence the responses of high‐affinity extrasynaptic receptors, such as NMDA or metabotropic receptors. Conversely, intra‐cleft glutamate transporters should significantly attenuate activation of synaptic transmission. On a larger neuropil scale, failure of >95% transporters is required for any significant elevation of glutamate (above 1‐2 μM) to occur. Our data shed light on fundamental biophysical constraints important for a better understanding of excitatory signal formation in central neural circuits.

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