Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease.

By J. Palop, Jeannie Chin, E. Roberson, Jun Wang, Myo Thwin, Nga Bien-Ly, Jong W. Yoo, Kaitlyn Ho, Gui-qiu Yu, A. Kreitzer and 3 more. Neuron, 2007

1,601 citations recorded by the source corpus.

Neural network dysfunction may play an important role in Alzheimer's disease (AD). Neuronal circuits vulnerable to AD are also affected in human amyloid precursor protein (hAPP) transgenic mice. hAPP mice with high levels of amyloid-beta peptides in the brain develop AD-like abnormalities, including cognitive deficits and depletions of calcium-related proteins in the dentate gyrus, a region critically involved in learning and memory. Here, we report that hAPP mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, which is associated with GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus. Many Abeta-induced neuronal alterations could be simulated in nontransgenic mice by excitotoxin challenge and prevented in hAPP mice by blocking overexcitation. Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to Abeta-induced neurological deficits in hAPP mice and, possibly, also in humans with AD.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Physiology

View Paper: https://www.semanticscholar.org/paper/6eef899d9ec4a765192187bf11ded0be677b6401

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Citations in the corpus

Hippocampal sharp wave‐ripple: A cognitive biomarker for episodic memory and planning (2015, neutral): “can be attenuated by reducing excitation (Palop et al., 2007).”
Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. (2012, background): “2011), the outer molecular layers of their dentate gyri have extensive sprouting of GABAergic terminals, and their granule cells receive an increased number of inhibitory inputs (Palop et al. 2007).”
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. (2010, neutral): “…several APP transgenic strains (Minkevi-ciene et al., 2009; Palop et al., 2007; Palop and Mucke, 2009) and have been associated with AD; the extent of their contribution to pathology, however, remains to be established (Minkeviciene et al., 2009; Palop et al., 2007; Palop and Mucke, 2009).”
Amyloid β-Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy (2009, background): “…induced seizures in APP transgenic mice (Del Vecchio et al., 2004; Palop et al., 2007) and morphological changes in hippocampal networks similar to reported after induced seizures (Palop et al., 2007), these studies provided no evidence for mechanisms underscoring increased seizure susceptibility.”
Advancing the understanding of autism disease mechanisms through genetics (2016, neutral): “However, E/I imbalance is a broad concept that is frequently observed in a wide variety of brain disorders including epilepsy, Alzheimer’s disease and schizophrenia 158–160 ; therefore, the contribution of E/I imbalance to ASD pathophysiology requires considerable refinement.”
Gamma frequency entrainment attenuates amyloid load and modifies microglia (2016, neutral): “Altered gamma has been observed in multiple brain regions in several neurological and psychiatric disorders, including a reduction in spontaneous gamma synchronization in patients with AD and reduced gamma power in multiple AD mouse models 4,5,8,9 .”
Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, positive): “…providing a novel mechanism by which accelerated spine loss, increased tau phosphorylation (Kocherhans et al. 2010), loss of network homeostasis (Palop et al. 2007; Palop and Mucke 2010), and earlier disease onset through loss of neuroprotective compensatory bandwidth (Korwek et al. 2009) can…”
Epilepsy and Cognitive Impairments in Alzheimer Disease (2009, background): “Our experimental data suggest that reducing tau levels is highly effective in preventing A -induced network dysfunction and cognitive deficits in vivo (Figure 3).(4,5) However, much more research is needed to further assess the efficacy and safety of this novel therapeutic strategy.”
Brain imaging in Alzheimer disease. (2012, background): “…cholinergic or other neurotransmitter up-regulation (DeKosky et al. 2002), aberrant sprouting of cholinergic fibers (Masliah et al. 2003), inefficiency in synaptic transmission (Stern et al. 2004), increased calcium influx, and evidence of excitotoxicity (Palop et al. 2007; Busche et al. 2008).”
Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. (2019, background): “Aberrant neural activity can also exacerbate the progression of AD pathology, which ultimately disrupt neural circuits involved in higher cognitive functions (Palop et al., 2007; Canter et al., 2016).”
Amyloid deposition is associated with impaired default network function in older persons without dementia (2009, neutral): “Recent molecular and electrophysiological studies in amyloid precursor protein (APP) transgenic mouse models may be relevant to our findings of abnormally increased activity in regions with high amyloid burden.”
Soluble oligomers of amyloid β-protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake (2009, positive): “significantly increase spontaneous non-convulsive seizure activity in cortical and hippocampal networks in APP transgenic mice (Palop et al., 2007).”
Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer’s Disease (2009, positive): “Ab elicits aberrant excitatory neuronal activity that is associated with remodeling of inhibitory circuits and an increased number of inhibitory synaptic contacts onto GCs in the DG (Palop et al., 2007).”