Investigating the Contribution of Hyperpolarization-Activated Mixed Cation Channels to the Role of Oriens-Lacunosum/Moleculare Interneurons in Oscillatory Activity of the Hippocampus Using Computational Modelling

The hippocampus is a brain structure implicated in memory formation and spatial navigation. Understanding the structure and function of the hippocampal system is important in developing an understanding of its functioning in behaviour and neurological disease. Inhibitory interneurons in the hippocampus serve a primary role in the generation of hippocampal network rhythms which have been linked to behaviour. One type of interneuron in the hippocampal CA1 region is the oriens-lacunosum/moleculare (O-LM) cell, which forms inhibitory synapses onto local pyramidal cells. O-LM cells express hyperpolarization-activated mixed cation currents (Ih) that contribute to cellular excitability and action potential generation. Although experimental investigations have implicated Ih in the activity of O-LM cells in hippocampal activity, it is currently unknown how Ih interacts with other voltage-gated channels and synaptic inputs to shape O-LM cell output. In this thesis, I develop and use computational models of O-LM cells that are constrained by experimental recordings to study how expression and distribution of Ih allows O-LM cells to be recruited in hippocampal networks. I first find that varying dendritic distributions of Ih in O-LM cell models can equally capture electrophysiological output of O-LM cells, so long as the total membrane current due to Ih is conserved. I then show that somatic or dendritic distributions of Ih can tune O-LM cell models to participate in different network rhythms expressed in hippocampus that have been implicated in either mnemonic or emotional behaviour. Finally, I develop a new set of multi-compartment models of O-LM cells using recently acquired experimental data. These models lead to a prediction of dendritic Ih expression in the set of O-LM cells from which the recordings were obtained. My work thus represents a link in the chain of elucidating how cellular electrophysiological properties of inhibitory interneurons allow them to perform their roles in hippocampal activity.Ph.D