Synchronization by Distal Dendrite-targeting Interneurons

Abstract

Synchronization among neurons arises from the cooperative interaction of various cell types through excitation and inhibition. The mechanisms behind this type of neuronal orchestration are as versatile as almost no other coordination task in the brain, making its comprehension heavily challenging. Among many others, the high number of involved cell types, the diversity of synaptic processes as well as the contribution of a multitude of ion channels and currents span the plurality of neuronal synchronization mechanisms in our brains. Focusing on two brain areas, the hippocampus and the neocortex, this thesis aims to understand the role of distal dendritetargeting interneurons in shaping pyramidal cell activity and the timing of their action potentials. The distribution of ion channels and synaptic receptors in pyramidal cell dendrites is extremely anisotropic. Thus, interneurons innervating the proximal or distal areas of the dendrites cause different effects in the target cell when activated. For example, the distal portions of the pyramidal cell dendrites contain one of the most prominent pacemaker channels: the hyperpolarizationactivated cyclic nucleotide-gated channels. These channels produce a cationic depolarizing current (Ih) and play an essential role in the regulation of neuronal excitability. Using computational modeling, this thesis shows how the amount of Ih in certain cell types determines their spike rate, synchrony as well as power and frequency of ongoing network oscillations. Moreover, since Ih differs between brain regions as well as cell types and location, this thesis electrophysiologically explores how Ih differs along the dorsoventral axis of hippocampus in oriens-lacunosum moleculare (OLM) cells, the main distal dendrite-targeting interneurons of that region. Utilizing the main distal dendrite-targeting interneuron of the neocortex, the Martinotti cell, this thesis also shows how a defined population of interneurons can be manipulated in order to control and align pyramidal cell firing. By providing the right amount and frequency of inhibition, Martinotti cells are able to synchronize trains of subtype-specific pyramidal cells. Using optogenetic approaches to activate/inactivate populations of Martinotti cells, these dendrite-targeting interneurons are shown to trigger rebound action potentials in pyramidal cells when temporally aligned. The rebound action potentials in turn are the result of strong inhibition by Martinotti cells, giving these distal dendrite-targeting interneurons the power to reset pyramidal cell firing. Overall, Martinotti cells and OLM cells show quite striking similarities in morphological, neurochemical and electrophysiological properties. Especially, their long axonal projections to upper layers as well as their low-threshold, slow spiking fashion and the accommodating firing make these distal dendrite-targeting interneurons so special for neuronal synchronization.