The role of the HCN2 channel in the mouse septohippocampal circuit

Brümmer, Manuela (2022): The role of the HCN2 channel in the mouse septohippocampal circuit. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels be-long to the superfamily of voltage gated ion channels. They are activated by hyperpolarization and modulated by cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) binding to the cyclic nucleotide-binding domain (CNBD). There are four isoforms of HCN channels, HCN1-4, that convey a depolarizing inward current, termed Ih, which is essential for a variety of physiological processes in the brain, such as the stabilization of the resting membrane potential, the regulation of firing properties, and the genera-tion of theta oscillations. In the central nervous system, HCN channels are ex-pressed for example in the hippocampus and in the medial septum (MS). The hippocampus and the MS are interconnected via GABAergic (gamma-aminobutyric acid), cholinergic, and glutamatergic projection neurons and form the septo-hippocampal system. This system is crucial for the generation and modulation of the theta rhythm, which is one of the most prominent synchro-nous rhythms in the brain and is characterized by a frequency of 4-12 Hz. Functionally, the theta rhythm is critically involved in information processing, rapid-eye-movement sleep (REM), and organization of cognitive processes like learning and memory. In this study, I knocked out HCN2 in distinct subsets of MS neurons by a lenti-viral-based system with the help of a Cre-dependent approach. Investigating GABAergic neurons, electrophysiological recordings showed that in Cre-injected animals Ih and the theta power of REM sleep in electroencephalogram (EEG) recordings were reduced. Hippocampal spatial behavior was unaltered, while the object recognition memory was impaired. The examination of an HCN2 knockdown pan-neuronal of the MS resulted in a significantly reduction of Ih current and theta power of REM sleep. Additionally, HCN2 knockdown led to an impairment in hippocampal-dependent reversal learning in the Water Cross Maze (WCM). These findings implicate an important influence of HCN2 in the MS on septo-hippocampal neurons and the generation of theta oscilla-tions in the hippocampus.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: HCN channels, hippocampus CA1, medial septum, GABAergic neurons, cholinergic neurons, glutamatergic neurons, behavior, EEG, theta rhythm, REM sleep, Water Cross Maze, social recognition test, object recognition test
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 3. Juni 2022
• 1. Bericht­erstatter:in: Biel, Martin