Fig 3. Dynamic chloride accumulation compromises the effectiveness of inhibition during balanced distal synaptic input.

(A) Inner left, schematic of the model, depicting excitatory synaptic input targeted toward the distal dendrite and inhibitory synapses targeted at the proximal dendrite. Left, average output firing rates over the course of a 1 s simulation as a function of balanced synaptic input for different pairs of E:I synaptic numbers (shades of green, right). Each pair resulted in a 5 Hz output following 5 Hz balanced input (as in Fig 2). Simulations were performed either with [Cl^-]_i able to vary dynamically (“dynamic chloride”, solid lines) or with [Cl^-]_i held at a constant value (“static chloride”, dashed lines). Insets with example voltage traces for simulation runs at 20 Hz input for both dynamic (top inset) and static (bottom inset) Cl^- as well as [Cl^-]_i for the dynamic Cl^- simulations (middle inset). These show that accounting for Cl^- dynamics results in obvious changes in spike timing. However, chloride dynamics did not result in large changes in output firing rates. (B) Inner left, schematic demonstrating excitatory and inhibitory inputs co-targeted toward the distal dendrite. Left, output firing rates following different balanced input frequencies with different pairs of E:I synaptic numbers (shades of blue, right) as in ‘A’, but with distally targeted inhibition. Dynamic Cl^- resulted in large changes to output firing rates (solid vs dashed lines) as well as spike timing (inset, example simulation runs). (C) Output firing rate given 20 Hz balanced input for different numbers of inhibitory synapses targeted to the proximal dendrite (left) or the distal dendrite (right). Adding more inhibitory synapses in the case of distally targeted inhibtion did not meaningfully impact the firing rate when Cl^- was dynamic. This was not the case for static Cl^- where increasing the number of inhibitory synapses continued to decrease output.