Don’t Overthink It: Is Excess Neural Activity Deleterious?
For some time now it has been suspected that neural hyperactivity might be linked to Alzheimer’s pathology. PET neuroimaging studies [1] have revealed that amyloid deposits appear first in the default mode network (DMN), which is the most active neural network in the human brain at rest.
Takeshi Iwatsubo of the University of Tokyo exploited optogenetics to selectively augment neural activity in specific neuroanatomic regions using a flash of light. Optogenetics is a powerful tool that allows both temporal and spatial control of neural activity in vivo. The results of Iwatsubo’s efforts were published in the latest (may) edition of Cell, demonstrating that five months of repeated optogenetic simulation in Alzheimer’s amyloid precursor protein (APP) transgenic mice more than doubled amyloid beta deposits in the hippocampus. The paper [2] abstract reads as follows:
In vivo experimental evidence indicates that acute neuronal activation increases Aβ release from presynaptic terminals, whereas long-term effects of chronic synaptic activation on Aβ pathology remain unclear. To address this issue, we adopted optogenetics and transduced stabilized step-function opsin, a channelrhodopsin engineered to elicit a long-lasting neuronal hyperexcitability, into the hippocampal perforant pathway of APP transgenic mice. In vivo microdialysis revealed a ∼24% increase in the hippocampal interstitial fluid Aβ42 levels immediately after acute light activation. Five months of chronic optogenetic stimulation increased Aβ burden specifically in the projection area of the perforant pathway (i.e., outer molecular layer of the dentate gyrus) of the stimulated side by ∼2.5-fold compared with that in the contralateral side. Epileptic seizures were observed during the course of chronic stimulation, which might have partly contributed to the Aβ pathology. These findings implicate functional abnormalities of specific neuronal circuitry in Aβ pathology and Alzheimer disease.
Optogenetics, allows neurons to be switched on or off at will in live animals by exploiting light sensitive channels called opsins. When a light-sensitive channel absorbs photons, it triggers a conformation change in the receptor, followed by calcium entry and membrane depolarization, allowing light to be coupled to the generation of action potentials at the biomolecular level.
Takeshi’s findings represent the first discovery of a concrete, mechanistic link between neuronal hyper-excitability and amyloid burden, the protein aggregate that is a hallmark of Alzheimer’s disease. These results confirm the suspicion that the most metabolically active areas of the brain are the first to succumb to Alzheimer’s pathology. The underlying hypothesis is also supported by previous work conducted by member’s of Takeshi’s team (published in Neuron, 2005) demonstrating that synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. The abstract for this earlier publication [3] reads as follows:
Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer’s disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.
Taken together, these findings strengthen the link between excessive neural activity and deleterious consequences for the brain. The findings also indirectly highlight the importance of sleep hygiene on cognitive health, since sleep plays an important role in synaptic downscaling, defined as, “a negative feedback response to chronic elevated network activity to reduce the firing rate of neurons”[4]. Sleep, therefore, transiently decreases global neuronal excitability and protects the brain from chronically elevated amyloid beta.
Dr. Nedergaard, a neurologist at the University of Rochester, led researchers to demonstrate that sleep drives the clearance of metabolites from the brain, including Abeta. Nedergaard also suggests that the primary function of sleep may be essentially to facilitate the removal of neurotoxic byproducts of metabolism that accumulate during wakefulness. The results of her investigation were published in the October edition of Science in 2013 [5].
[1] Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci USA. 2004;101(13):4637-42.
[2] Yamamoto K, Tanei Z, Hashimoto T, et al. Chronic optogenetic activation augments aβ pathology in a mouse model of Alzheimer disease. Cell Rep. 2015;11(6):859-65.
[3] Cirrito JR, Yamada KA, Finn MB, et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005;48(6):913-22.
[4] Siddoway B, Hou H, Xia H. Molecular mechanisms of homeostatic synaptic downscaling. Neuropharmacology. 2014;78:38-44.
[5] Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-7.