Extracellular diffusivity determines contribution of high-versus low-affinity receptors to neural signaling

Diffusion-weighted magnetic resonance imaging detects physiological changes in the human brain by highlighting alterations in local diffusivity. However, the causal link between brain tissue diffusivity and neural activity is poorly understood. Synaptic physiology studies in vitro coupled with biophysical modeling have suggested that extracellular diffusion affects the spatial profile of receptor activation during synaptic discharges. Here, we attempt to address this issue more directly, by recording synaptic currents from individual cells in acute brain slices while reducing the bath medium diffusivity by 25-30% (measured with two-photon microscopy) using inert dextran molecules. We find that retarding extracellular diffusion increases the activation of high-affinity NMDA, but not low-affinity AMPA, receptors in response to remote, spontaneous or evoked, synaptic releases of the common excitatory neurotransmitter glutamate. The results suggest that variations in extracellular diffusivity could reflect an altered contribution of higher- versus lower-affinity receptor types to the network activity of synaptic circuits.