Distinct extracellular signatures of active-dendritic chemical and electrical synapses differentially contribute to ripple-frequency oscillations

Abstract

Extracellular field potentials across brain regions exhibit distinct signatures that depend on several region-specific attributes, including spatiotemporal patterns of afferent inputs, anatomical and physiological properties of the different cells, density and local connectivity of cells, electrode location, and properties of the extracellular matrix. Analyses and interpretations of local field potentials (LFPs) have traditionally been assumed to be solely based on chemical synaptic inputs impinging on the active structure. The influence of gap junctional inputs on LFP signatures have remain largely unexplored. The central aim of this thesis is to understand the fundamental relationship between neuronal inputs and LFPs when different stimuli impinge on active dendrites through chemical synapses vs. gap junctions. In the first part of the thesis, we address a fundamental question on gap junctional inputs contributions to LFPs, while also exploring the similarities and distinctions between how chemical synapses and gap junctions shape extracellular signatures. We employed morphologically realistic conductance-based neuronal models and placed a 3D array of extracellular electrodes spanning the somato-dendritic stretch. We computed LFPs when basal dendrites were simulated with inputs of different temporal patterns and analysed the spatiotemporal profiles of LFPs for gap junctions vs. chemical synapses. We found a striking reversal in the polarity of extracellular potentials associated with synchronous inputs through chemical synapses vs. gap junctions onto active dendrites. Whereas excitatory synchronous inputs through chemical synapses yielded a negative deflection in proximal electrodes, those through gap junctions manifested a positive deflection. With rhythmic inputs arriving through gap junctions, we found strong suppression of LFP power at higher frequencies. There were frequency-dependent differences in the spike phase associated with the LFP, depending on whether inputs arrived through gap junctions or chemical synapses. All observed differences in LFPs were mediated by the relative dominance of synaptic currents vs. voltage-driven transmembrane currents with chemical synapses vs. gap junctions, respectively. The second part of the thesis focuses specifically on the high-frequency range of LFPs to quantitatively evaluate several competing models for the emergence of ripple oscillations. Ripples form a component of sharp-wave ripple complexes that have been implicated in memory consolidation. We analysed the characteristics of extracellular potentials associated with individual or combined contributions of different dendritic inputs through chemical synapses vs. gap junctions, aiming to quantitatively probe the origins of ripple oscillations in the hippocampus. We observed distinct ripple characteristics in extracellular potentials with different input types, in a manner that was also dependent on the active dendritic currents, pattern of input, and the mode of synaptic transmission. Among all the individual inputs, we found contributions from the local inhibitory network to be maximal with gap junctional inputs making the weakest contribution to ripple–frequency oscillations. While perisomatic inhibitory inputs play a critical role in mediating ripple oscillations, gap junctional and other excitatory inputs could play modulatory roles in shaping ripples through synergistic interactions amongst all inputs. Together, these results demonstrate distinct roles for gap junctional vs. chemical synaptic inputs in shaping extracellular signatures. Therefore, LFP interpretations should consider their collective impact on extracellular potentials that is contributing to specific aspects of network physiology. We quantitatively demonstrate the differential dependencies of hippocampal ripple-frequency oscillations on a diverse set of local as well as afferent inputs and suggest a unified framework involving disparate inputs for the generation of ripple oscillations.