Objective Intra-retinal placement of stimulating electrodes can provide close and stable proximity to target neurons. We assessed improvement in stimulation thresholds and selectivity of the direct and network-mediated retinal stimulation with intraretinal electrodes, compared to epiretinal and subretinal placements. Approach Stimulation thresholds of the retinal ganglion cells (RGCs) in wild-type rat retina were measured using patch-clamp technique. Direct and network-mediated responses were discriminated using various synaptic blockers. Main results Three types of RGC responses were identified: short latency (SL, τ<5ms) originating in RGCs, medium latency (ML, 3<τ<70ms) originating in the inner nuclear layer and long latency (LL, τ>40ms) originating in photoreceptors. Cathodic epiretinal stimulation exhibited the lowest threshold for direct RGC response and the highest direct selectivity (network/direct thresholds ratio), exceeding a factor of 3 with pulse durations below 0.5ms. For network-mediated stimulation, the lowest threshold was obtained with anodic pulses in OPL position, and its network selectivity (direct/network thresholds ratio) increased with pulse duration, exceeding a factor of 4 at 10ms. Latency of all three types of responses decreased with increasing strength of the stimulus. Significance These results define optimal range of pulse durations, pulse polarities and electrode placement for the retinal prostheses aiming at direct or network-mediated stimulation of RGCs.

Summary Benzodiazepines (BZs) allosterically modulate γ-aminobutyric acid type-A receptors (GABAARs) to increase inhibitory synaptic strength. Diazepam binding inhibitor (DBI) protein is a BZ site ligand expressed endogenously in the brain, but functional evidence for BZ-mimicking positive modulatory actions has been elusive. We demonstrate an endogenous potentiation of GABAergic synaptic transmission and responses to GABA uncaging in the thalamic reticular nucleus (nRT) that is absent in both nm1054 mice, in which the Dbi gene is deleted, and mice in which BZ binding to α3 subunit-containing GABAARs is disrupted. Viral transduction of DBI into nRT is sufficient to rescue the endogenous potentiation of GABAergic transmission in nm1054 mice. Both mutations enhance thalamocortical spike-and-wave discharges characteristic of absence epilepsy. Together these results indicate that DBI mediates endogenous nucleus-specific BZ-mimicking (“endozepine”) roles to modulate nRT function and suppress thalamocortical oscillations. Enhanced DBI signaling might serve as a novel therapy for epilepsy and other neurological disorders.

Parvalbumin-expressing fast-spiking (FS) cells are interconnected via GABAergic and electrical synapses and represent a major class of inhibitory interneurons in the neocortex. Synaptic connections among FS cells are critical for regulating network oscillations in the mature neocortex. However, it is unclear whether synaptic connections among FS interneurons also play a central role in the generation of patterned neuronal activity in the immature brain, which is thought to underlie the formation of neocortical circuits. Here, we investigated the developmental time course of synaptogenesis of FS cell in mouse visual cortex. In layer 5/6 (L5/6), we recorded from two or three FS and/or pyramidal neurons (P) to study the development of electrical and chemical synaptic interactions from postnatal day 3 (P3) to P18. We detected no evidence for functional connectivity for FS-FS or FS-P pairs at P3–4. However, by P5–6, we found 20% of FS pairs were electrically coupled and 24% of pairs were connected via GABAergic synapses and by P15–18, 42% of FS pairs had established functional electrical synapses and 47% of FS pairs were connected via GABAergic synapses. FS cell GABAergic inhibition of pyramidal cells showed a similar developmental time line, but no electrical coupling was detected for FS-P pairs. We found that synaptogenesis of electrical and GABAergic connection of FS cells takes place in the same period. Together, our results suggest that chemical and electrical connections among FS cells can contribute to patterned neocortical activity only by the end of the first postnatal week.

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It is well known that spiking neurons can produce action potentials in response to extracellular stimulation above certain threshold. It is widely assumed that there is no upper limit to somatic stimulation, except for cellular or electrode damage. Here we demonstrate that there is an upper stimulation threshold, above which no action potential can be elicited, and it is below the threshold of cellular damage. Existence of this upper stimulation threshold was confirmed in retinal ganglion cells (RGCs) at pulse durations ranging from 5 to 500 μs. The ratio of the upper to lower stimulation thresholds varied typically from 1.7 to 7.6, depending on pulse duration. Computational modeling of extracellular RGC stimulation explained the upper limit by sodium current reversal on the depolarized side of the cell membrane. This was further confirmed by experiments in the medium with a low concentration of sodium. The limited width of the stimulation window may have important implications in design of the electro-neural interfaces, including neural prosthetics