Hippocampal network and inhibitory neuron dysfunction in age and disease

Abstract

Aging and Alzheimer’s disease (AD) are two highly intertwined pathological processes. Indeed, one of the highest risk factors for developing AD is age. Mechanistically, it has been suggested that remodeling of inhibitory neuron function causes the disruption of the homeostatic excitatory/inhibitory balance that is at the basis for effective information processing in the central nervous system. In the hippocampus proper and medial entorhinal cortex (MEC), a plethora of inhibitory neurons is tailored to orchestrate input/output conversion in excitatory neurons, thereby supporting hippocampal-dependent cognitive processes, like episodic memory and navigation. Furthermore, altered inhibitory function is a major contributor to aberrant oscillatory activity recorded by means of electroencephalograms and local field potentials (LFP) in the hippocampal system of both aged and AD brains. Hence, therapeutic approaches devoted to the restoration of inhibitory tone, with the aim of normalizing oscillatory correlates of cognitive processes, have emerged as a strategy to counteract the deleterious effects of aging and AD. In particular, theta and gamma oscillations have been the preferred target of investigation and manipulation. Nonetheless, more evidence is required to understand how age and AD impact oscillatory activity in the hippocampus and MEC, and whether inhibitory-neurons driven rhythmogenesis is a viable strategy to alleviate the cognitive burden associated with both conditions. <br /> Here, I probed the hippocampal network of aged PV-Cre::WT mice and their APPswe/PS1dE9 (PV-Cre::APP/PS1) transgenic littermates, used as model of familial AD. To do so, I employed LFP recordings, and LFP recordings coupled with optogenetic stimulation of local parvalbumin-positive (PV⁺) interneurons in the CA1 compartment of the hippocampus of awake, freely moving animals. I showed that theta oscillations linearly decrease with age in PV-Cre::WT animals, but not in PV-Cre::APP/PS1 mice, which is indicative of inhibitory neuron dysfunction. Interestingly, theta-gamma coupling measured as a modulation index (MI) in the <em>stratum lacunosum moleculare</em> (SLM) was reduced in PV-Cre::APP/PS1 animals, showing that feedback communication between the hippocampus and the MEC is altered. Besides, I detected an age-dependent linear increase in the MI of PV-Cre::WT animals, but not in PV-Cre::APP/PS1 animals, indicating that age-related network remodeling differs between healthy and AD conditions. Next, I investigated the effects of optogenetically stimulating hippocampal PV⁺ neurons of aged PV-Cre::WT and PV-Cre::APP/PS1 mice during memory tasks probing recognition-, working- and spatial memory. Here, optogenetic stimulation of PV⁺ interneurons in aged PV-Cre::WT and PV-Cre::APP/PS1 animals was sufficient to rescue cognitive deficits of APP/PS1 animals, but not WT animals, in a spatial memory task. Furthermore, I showed that somatostatin-positive (SOM⁺) long-range inhibitory projections between the hippocampus and the MEC, a poorly described neuronal population, are impaired in SST-Cre::APP/PS1 mice. This was concomitant with a reduction of local SOM-immunoreactivity in the MEC. Potentially, the structural and functional alterations of local and long-range projecting SOM⁺ neurons underlie the alterations of theta-gamma coupling observed in APP/PS1 animals. <br /> The results presented in this thesis thus contribute to the existing knowledge about oscillatory aberrations in health and disease. In addition, these results provide new perspectives on the mechanisms that cause network dysfunction and cognitive deficits in healthy and AD-like conditions.