Modulation of the hyperpolarization activated cationic current (Ih) and subthreshold resonance in neocortical neurons

Giles, Cory Victor (2005) Modulation of the hyperpolarization activated cationic current (Ih) and subthreshold resonance in neocortical neurons. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Resonance is a biophysical characteristic of a subset of neurons in which the voltage response of oscillating input peaks at a preferred frequency. Given the widespread distribution of histaminergic neurons and the known physiology of histamine receptors in the CNS, it was hypothesized that histamine modulates the resonance of pyramidal neurons by shifting the activation and kinetics of the hyperpolarization activated cationic current, Ih. -- Employing standard whole cell voltage clamp recording, investigation of the modulation of Ih was confounded by a time dependent hyperpolarizing shift of Ih. The addition of cAMP to the recording pipette prevented rundown and resulted in a depolarizing shift in Ih activation consistent with an important role for intracellular cAMP in the maintenance and modulation of Ih. -- In the presence of cAMP in the pipette, bath application of histamine, 8-bromo-cAMP, and forskolin, mimicked cAMP-induced changes in Ih. Histamine's action was mimicked by amthamine (H₂ agonist), blocked by tiotidine (H₂ antagonist), and occluded by forskolin, consistent with an H₂ receptor-mediated activation of adenylyl cyclase. H7, a nonspecific protein kinase inhibitor, blocked both the forskolin and histamine-induced effects on Ih consistent with involvement of a phosphorylation event. -- Using the Impedance Amplitude Profile (ZAP) methodology to profile the resonant properties of pyramidal neurons, histamine increased both the resonant frequency (fres) and its magnitude (Q) in a concentration-dependent manner that closely resembled histamine's action on Ih. This was confirmed by application of ZD-7288, an -- irreversible blocker of Ih, which blocked both the histamine-induced action and resonance. -- It is concluded that histamine, acting via H₂ receptor activation of adenylyl cyclase and possibly a protein kinase, shifts the activation of h to more depolarized potentials. This action modulates the resonant behaviour of these neurons, which in tum can influence their oscillatory properties and consequently aid in the synchronization of larger neuronal networks.

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