Mechanisms Of Dopaminergic, Histaminergic, And Glutamatergic Neuromodulation Within The Medial Entorhinal Cortex
Date of Award
Doctor of Philosophy (PhD)
The medial entorhinal cortex (MEC) is a critical region for both limbic functions as well as learning and memory. In addition to these normal processes, the MEC is also implicated in several disorders including epilepsy, Alzheimer’s disease, and several neuropsychiatric disorders. The MEC’s function and role in various disorders is intimately related to its underlying cellular activity. The primary neuronal cell types in this region consist of glutamatergic principle cells and GABAergic local inhibitory interneurons. This dissertation consists of three aims related to the neuromodulation of these cells located in the superficial layers of the MEC—the primary input source to the hippocampus. The first aim addresses how dopamine (DA) alters GABAergic transmission. The second aim also considers GABAergic transmission but examines its modulation by histamine (HA). Finally, the third aim investigates mechanisms of group I metabotropic glutamate receptor(mGluR)-induced increases in layer III principal cell excitability. For Study 1, exogenous application of DA increases spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from layer II neurons. This increase is mediated by a promiscuous interaction with the α1 adrenergic receptors (α1 ARs) found on the MEC interneurons. Application of amphetamine to elevate extracellular DA concentrations mimic theses effects in an α1 AR-dependent fashion. Activation of interneuron α1 AR-induced depolarization is mediated by inhibition of inwardly rectifying K+ channels (Kirs). For Study 2, exogenous application of HA increases sIPSCs recorded from layer II principal neurons. This increase requires both H1 and H2 receptors located on GABAergic interneurons. The magnitude of HA-induced depolarization is significantly larger within one class of tested interneurons and HA-induced depolarization of interneurons involves both the inhibition of (Kirs) and activation of a TTX-insensitive Na+ current. For Study 3, activation of group I mGluRs increases action potential firing, depolarization and generation of inward currents in layer III pyramidal neurons. This increase is sensitive to antagonists for both mGluR1 and mGluR5, indicating the functional presence of both receptors. The mGluR-induced currents are mediated by a non-selective cation channel that contains TRPC4 and TRPC5 subunits.
Cilz, Nicholas Ian, "Mechanisms Of Dopaminergic, Histaminergic, And Glutamatergic Neuromodulation Within The Medial Entorhinal Cortex" (2017). Theses and Dissertations. 2188.