Quantifying Biomarkers of Cognitive Dysfunction and Neuronal Network Hyperexcitability in Mouse Models of Alzheimer’s Disease: Depletion of Calcium-Dependent Proteins and Inhibitory Hippocampal Remodeling
ABSTRACT High levels of Aβ impair neuronal function at least in part by disrupting normal synaptic transmission and causing dysfunction of neural networks. This network dysfunction includes abnormal synchronization of neuronal activity resulting in epileptiform activity. Over time, this aberrant network activity can lead to the depletion of calcium-dependent proteins, such as calbindin, Fos, and Arc, and compensatory inhibitory remodeling of hippocampal circuits, including GABAergic sprouting and ectopic expression of the inhibitory neuropeptide Y (NPY) in dentate granule cells. Here we present detailed protocols for detecting and quantifying these alterations in mouse models of Alzheimer's disease (AD) by immunohistochemistry. These methods are useful as surrogate measures for detecting chronic aberrant network activity in models of AD and epilepsy. In addition, since we have found that the severity of these changes relates to the degree of Aβ-dependent cognitive impairments, the protocols are useful for quantifying biomarkers of cognitive impairment in mouse models of AD.
- SourceAvailable from: Didac Vidal-Piñeiro
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- "In accordance with their fundamental role in mechanisms of neuroplasticity, GABA and glutamate imbalances   have been reported in the abovementioned conditions characterized by DMN dysfunction. For example, in Alzheimer's disease neuroplasticity is altered in association with a glutamate/GABA microcircuit dysfunction, which additionally shows complex interactions with Amyloid-beta deposition . "
ABSTRACT: The Default Mode Network (DMN) is severely compromised in several psychiatric and neurodegenerative disorders where plasticity alterations are observed. Glutamate and GABA are the major excitatory and inhibitory brain neurotransmitters respectively and are strongly related to plasticity responses and large-scale network expression. To investigate whether regional Glx (Glutamate + Glutamine) and GABA could be modulated within the DMN after experimentally-controlled induction of plasticity and to study the effect of intrinsic connectivity over brain responses to stimulation. We applied individually-guided neuronavigated Theta Burst Stimulation (TBS) to the left inferior parietal lobe (IPL) in-between two magnetic resonance spectroscopy (MRS) acquisitions to 36 young subjects. A resting-state fMRI sequence was also acquired before stimulation. After intermittent TBS, distal GABA increases in posteromedial DMN areas were observed. Instead, no significant changes were detected locally, in left IPL areas. Neurotransmitter modulation in posteromedial areas was related to baseline fMRI connectivity between this region and the TBS-targeted area. The prediction of neurotransmitter modulation by connectivity highlights the relevance of connectivity patterns to understand brain responses to plasticity-inducing protocols. The ability to modulate GABA in a key core of the DMN by means of TBS may open new avenues to evaluate plasticity mechanisms in a key area for major neurodegenerative and psychiatric conditions. Copyright © 2015 Elsevier Inc. All rights reserved.Brain Stimulation 04/2015; DOI:10.1016/j.brs.2015.04.005 · 5.43 Impact Factor
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- "Tissue preparation and in situ hybridization were performed as described (Palop et al., 2011a, 2011b). Antisense and sense RNA probes were generated from linearized plasmids (NCBI#: BE944238 for Nav1.1 and AI839069 for Nav1.6) containing DNA sequences for Nav1.1 (327 base pairs) or Nav1.6 (289 base pairs) with T3 and T7 polymerase (Promega) and premixed RNA-labeling nucleotides containing digoxigenin (Roche Molecular Biochemicals). "
ABSTRACT: Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuron-specific and PV cell-predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD.Cell 04/2012; 149(3):708-21. DOI:10.1016/j.cell.2012.02.046 · 33.12 Impact Factor