Optogenetic Modulation of Beta Amyloid-Induced Brain Network Changes in the Mouse Hippocampus

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterised by progressive cognitive decline and severe memory loss. Currently, AD presents as a major global health concern due to the lack of efficacious treatments and a growing aging population. While considerable research effort has focused on the dysfunction of excitatory neurotransmitter systems in the progression of AD, increasing evidence now delineates a reciprocal role of inhibitory neurotransmitter dysfunction in the disease pathogenesis. GABA comprises the primary inhibitory neurotransmitter of the brain that is essential in the regulation of brain network activity and the maintenance of the excitatory-inhibitory (E/I) balance of neural systems. In AD, this GABA signalling system has been shown to undergo significant remodelling and dysfunction leading to an E/I imbalance in the hippocampus, further inducing cognitive deficits. Optogenetics provides a spatiotemporally precise mechanism for the selective modulation of GABAergic activity, potentially providing therapeutic benefits to the AD brain. This study aimed to investigate the behavioural and cellular effects induced by optogenetic activation of GABA cells in the CA1 hippocampal region in an Aβ1-42-injected in vivo model of AD. To evaluate these effects, mice expressing channelrhodopsin-2 (ChR2) in GABAergic cells in the CA1 hippocampal region received optogenetic stimulation (470 nm) prior to the onset of Aβ1-42-induced neuropathology and further behavioural testing 7 days poststimulation to examine hippocampal function. We observed that this stimulation of GABAergic cells in the CA1 region partially attenuated Aβ1-42-induced spatial memory deficits. Additionally, the optogenetic stimulation of GABAergic cells attenuated Aβ1-42-induced pyramidal cell loss in the CA1 and modulated Aβ1-42-induced alterations in a2, a5 and g2 expression in the CA1 hippocampal region. Moreover, the current study employed FluoVolt and GCaMP membrane potential fluorescent probes in an in vitro primary culture model to characterise the Aβ1-42-induced alterations in neuronal activity that occur in AD. Our data provides further insight into the GABAergic remodelling that occurs in AD and demonstrates the neuroprotective and cognition-enhancing effects of optogenetic activation of GABAergic cells prior to the onset of Aβ neuropathology, potentially by restoration of the hippocampal E/I balance in the AD brain. Furthermore, this study demonstrates the therapeutic potential of optogenetic neuronal modulation for the treatment of AD.