Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease.
Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage.
School of Computer Science, University of Birmingham Birmingham, UK.
Mark S
MS
Rowan
Department Physiology and Pharmacology, State University of New York Downstate Medical Center Brooklyn, NY, USA ; Department Neurobiology, Yale University School of Medicine New Haven, CT, USA.
Samuel A
SA
Neymotin
Department Physiology and Pharmacology, State University of New York Downstate Medical Center Brooklyn, NY, USA ; Department Neurology, State University of New York Downstate Medical Center Brooklyn, NY, USA ; Department Neurology, Kings County Hospital Center Brooklyn, NY, USA.
William W
WW
Lytton
Alzheimer's disease; computer modeling; electrostimulation; homeostasis; information transfer; neocortex; neuronal networks; synaptic scaling