Molecular changes in brain aging and Alzheimer's disease are mirrored in experimentally silenced cortical neuron networks

Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Biomedical Research Center, Baltimore, MD 21224, USA.
Neurobiology of aging (Impact Factor: 5.01). 10/2010; 33(1):205.e1-18. DOI: 10.1016/j.neurobiolaging.2010.08.012
Source: PubMed


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.

Download full-text


Available from: Yongqing Zhang,
  • Source
    • "Notably, IP3 receptor signaling is dysregulated in AD model mice, and Ryanodine receptor is upregulated in AD-derived tissue, in AD mice, and upon stress, leading to enhanced release of calcium into the cytosol and decreased excitability due to activation of SK channels (Stutzmann et al., 2004, 2006; Liu et al., 2012; Demuro and Parker, 2013). In sum, AD shares with other NDDs a loss of neuronal activation long before neuronal degeneration, and possibly also before loss of synapses (Gleichmann et al., 2012). However, due to a relative lack of experimental data concerning neuronal subpopulations particularly vulnerable to AD, it is currently not possible to relate firing properties of susceptible neurons to their silencing and degeneration in AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases (NDDs) involve years of gradual preclinical progression. It is widely anticipated that in order to be effective, treatments should target early stages of disease, but we lack conceptual frameworks to identify and treat early manifestations relevant to disease progression. Here we discuss evidence that a focus on physiological features of neuronal subpopulations most vulnerable to NDDs, and how those features are affected in disease, points to signaling pathways controlling excitation in selectively vulnerable neurons, and to mechanisms regulating calcium and energy homeostasis. These hypotheses could be tested in neuronal stress tests involving animal models or patient-derived iPS cells. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(5):901-910. DOI:10.1016/j.neuron.2014.12.063 · 15.05 Impact Factor
  • Source
    • "ment and neurodegenerative disease (Burke and Barnes 2010; Foster 2012; Gleichmann et al. 2012; Selkoe 2002; Waites and Garner 2011). Even Alzheimer's disease is being considered a synaptic disease (Nimmrich and Ebert 2009; Pozueta et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Basal forebrain (BF) cholinergic neurons participate in a number of cognitive processes that become impaired during aging. We found that age-related enhancement of Ca(2+) buffering in rat cholinergic BF neurons was associated with impaired performance in the water maze spatial learning task (Murchison et al. 2009). One way that altered Ca(2+) buffering could contribute to cognitive impairment involves synaptic function. Here we show that synaptic transmission in the BF is altered with age and cognitive status. We have examined the properties of spontaneous post-synaptic currents (sPSCs) in cholinergic BF neurons that have been mechanically dissociated without enzymes from behaviorally characterized F344 rats. These isolated neurons retain functional presynaptic terminals on their somata and proximal dendrites. Using whole-cell patch-clamp recording, we show that sPSCs and miniature PSCs (mPSCs) are predominately GABAergic (bicuculline sensitive) and in all ways closely resemble PSCs recorded in a BF in vitro slice preparation. Adult (6-7 month) and aged (22-24 month) male rats were cognitively assessed using the water maze. Neuronal phenotype was identified post-hoc using single-cell RT-PCR. The frequency of sPSCs was reduced during aging, and this was most pronounced in cognitively impaired subjects. This is the same population that demonstrated increased intracellular Ca(2+) buffering. We also show that increasing Ca(2+) buffering in the synaptic terminals of young BF neurons can mimic the reduced frequency of sPSCs observed in aged BF neurons.
    Journal of Neurophysiology 10/2013; 111(2). DOI:10.1152/jn.00129.2013 · 2.89 Impact Factor
  • Source
    • "In animals, an alteration of SRIF systems is observed during normal aging (Stanley et al., 2012) and pathological models of aging. In human a similar specific dysregulation is observed in normal pathological disorders such as some neurodegenerative and psychiatric diseases (Glorioso et al., 2011; Gleichmann et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Somatostatin is highly expressed in mammalian brain and is involved in many brain functions such as motor activity, sleep, sensory, and cognitive processes. Five somatostatin receptors have been described: sst(1), sst(2) (A and B), sst(3), sst(4), and sst(5), all belonging to the G-protein-coupled receptor family. During the recent years, numerous studies contributed to clarify the role of somatostatin systems, especially long-range somatostatinergic interneurons, in several functions they have been previously involved in. New advances have also been made on the alterations of somatostatinergic systems in several brain diseases and on the potential therapeutic target they represent in these pathologies.
    Frontiers in Endocrinology 12/2012; 3:154. DOI:10.3389/fendo.2012.00154
Show more