Feed-forward Inhibitory Circuits in Hippocampus and Their Computational Role in Fragile X Syndrome
Date of Award
Doctor of Philosophy (PhD)
Feed-forward inhibitory (FFI) circuits are canonical neural microcircuits. They are unique in that they are comprised of excitation rapidly followed by a time-locked inhibition. This sequence provides for a powerful computational tool, but also a challenge in the analysis and study of these circuits. In this work, mechanisms and computations of two hippocampal FFI circuits have been examined. Specifically, the modulation of synaptic strength of the excitation and the inhibition is studied during constant-frequency and naturalistic stimulus patterns to reveal how FFI circuit properties and operations are dynamically modulated during ongoing activity. In the first part, the FFI circuit dysfunction in the mouse model of Fragile X syndrome, the leading genetic cause of autism, is explored. The balance between excitation and inhibition is found to be markedly abnormal in the Fmr1 KO mouse, leading to failure of FFI circuit to perform spike modulation tasks properly. The mechanisms underlying FFI circuit dysfunction are explored and a critical role of presynaptic GABAB receptors is revealed. Specifically, excessive presynaptic GABA receptor signaling is found to suppress GABA release in a subset of hippocampal interneurons leading to excitation/inhibition imbalance. In the second part, the dynamic changes during input bursts are explored both experimentally and in a simulated circuit. Because of the short-term synaptic plasticity of individual circuit components, the burst is found to play an important role in the modulating precision of the output cell spiking. The role of dynamics balance of excitation and inhibition during bursts in output spiking precision is further explored. Overall, the balance of excitation and inhibition is found to be critical for FFI circuit performance.
Vitaly A. Klyachko
Tim Holy, Barani Raman, Bruce Carlson, James Heuttner,
Permanent URL: https://doi.org/10.7936/K74T6GMW