Cellular and network mechanisms in neurodegenerative disorders : neurotoxicity and rescue strategies

Abstract: The brain can be described as a complex network and its functioning depends on an efficient communication between all its components. Large-scale communication is made possible by neuronal-network oscillations. Oscillations in the gamma-frequency range (30-80 Hz) are associated with cognitive functions such as attention, working memory, sensory perception and long-term memory encoding and recall. These oscillations occur in the neocortex and hippocampus, and are known to be impaired in many diseases displaying cognitive-deficit symptoms, including neurodegenerative diseases. In the studies contained in this thesis we investigate basic neuronal mechanisms involved in the generation of gamma oscillations and their disruption in models of Alzheimer’s disease and Parkinson’s disease. Moreover, acting pharmacologically on different pathways, we try to prevent and/or rescue the impairment of the cognition-relevant rhythm and its behavioral consequences. In paper I we investigate whether the deleterious effects of amyloid-β peptide on cellular, network and behavioral level can be either prevented or rescued by targeted activation of the proteasome through the modulation of calcium dynamics. The use of mouse hippocampal slices, Drosophila fly models and induced pluripotent stem cells from AD patients showed that the inhibition of T-type calcium channels could be an effective therapeutic approach for AD and, potentially, other amyloidogenic brain diseases. In paper II we study brain hypometabolism and insulin resistance, both known to be risk factors for and common outcomes of amyloid-β peptide accumulation. The synergistic use of pyruvate, as an alternative source of energy, and insulin, to counteract insulin resistance, is efficient in rescuing and preventing synaptic and network dysfunction induced by acute application of amyloid-β peptide on mice hippocampal slices. In paper III we examine the role of histamine as a potential rhythmogenic neurotransmitter. In rat hippocampal slices the perfusion of histamine generates transient dose-dependent gamma oscillations, and this action seems to be dependent on the H1 receptor. Our data suggest that the generation of gamma oscillations may depend on H1 receptor-mediated inhibition of KCNQ channels. Lastly, in paper IV we study network activity and behavior of a Parkinson’s disease mouse model. The striatal injection of 6-hydroxidopamine disrupts the endogenous circadian rhythm of mice, reduces their motor activity and degrades gamma oscillations. Systemic administration of a histamine H3 receptor antagonist rescues normal rest/activity cycle and memory impairment underlain by gamma oscillations disruption.