Molecular changes in brain aging and Alzheimer's disease are mirrored in experimentally silenced cortical neuron networks.
Activity-dependent modulation of neuronal gene expression promotes neuronal survival and plasticity, and neuronal network activity is perturbed in aging and Alzheimer's disease (AD). Here we show that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca(2+) signaling; alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca(2+)-mediated degeneration.
Gleichmann
Marc
M
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Biomedical Research Center, Baltimore, MD 21224, USA.
Zhang
Yongqing
Y
Wood
William H
WH
Becker
Kevin G
KG
Mughal
Mohamed R
MR
Pazin
Michael J
MJ
van Praag
Henriette
H
Kobilo
Tali
T
Zonderman
Alan B
AB
Troncoso
Juan C
JC
Markesbery
William R
WR
Mattson
Mark P
MP
D000375:Aging / Q000235:genetics* / Q000502:physiology*; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000503:physiopathology*; D004597:Electroshock; D004734:Energy Metabolism / Q000235:genetics; D004777:Environment; D015870:Gene Expression; D006801:Humans; D007395:Interneurons / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000502:physiology; D009415:Nerve Net / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000235:genetics; D020813:Receptor, trkB / Q000502:physiology; D009435:Synaptic Transmission
D016202:N-Methylaspartate; D020813:Receptor, trkB