Bi-directional Control of Synaptic Input Summation and Spike Generation by GABAergic Inputs at the Axon Initial Segment / 神经科学通报·英文版

Differing from other subtypes of inhibitory interneuron, chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment (AIS) of targeted pyramidal cells (PCs). However, the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved. Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs, we quantitatively demonstrate that the onset-timing of AIS-GABAergic input, relative to dendritic excitatory glutamatergic inputs, determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC. More specifically, AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+ channels on summed synaptic excitation when they precede glutamatergic inputs by >15 ms, while for nearly concurrent excitatory inputs, they primarily produce a shunting inhibition at the AIS. Thus, our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.

Towards the Replacement Therapy Using Neural Stem/Progenitor cells for Neurological Disorders: Strategies to Enhance Therapeutic Capacity of Transplantation Approaches

Transplantation of neural stem/progenitor cells (NPC) holds potential to improve functional outcomes in various neurological disorders. It seems more difficult than previously envisioned, however, to functionally replace the lost neural cells by grafted NPCs. A lack of appropriate developmental cues in the injured tissue contributes to the failure to guide the NPCs to survive, differentiate, grow axons, and functionally integrate to the host neural circuit. Therefore, we need to design possible strategies to recapitulate the developmental processes for the grafted NPCs to fully mature into functional neural cells. To enhance survival of NPCs following transplantation, pharmacological treatments targeting apoptosis and inflammation can be combined with transplantation. Genetic overexpression of prosurvival genes or growth factors can also improve survival. In vitro predifferentiation not only provides neural cells of a specific lineage in high purity but also greatly reduces chances of a tumor formation. Genetic overexpression of various transcription factors or manipulating molecular microenvironment of the host can also be tried to force differentiation of NPCs to a desired lineage. Pharmacological application to overcome myelin inhibition or enzymatic degradation of the inhibitory extracellular matrix will enhance axonal growth of NPC-derived neurons. Increasing synaptic activity by behavioral training or patterned electrical stimulation may promote proper development of synaptic integration and myelination of the axon. A thorough understanding of cellular and molecular aspects of neural development will help design more sophisticated strategies to enhance therapeutic capacity of NPC transplantation to reconstruct the damaged neural circuit.