ArticleMolecular psychiatry2024
Dopamine neuron degeneration in the Ventral Tegmental Area causes hippocampal hyperexcitability in experimental Alzheimer's Disease.
Article in Molecular psychiatry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- Neurobiological mechanisms of 40-Hz stimulation in Alzheimer's disease: evidence, heterogeneity, and constraints.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Parvalbumin interneurons in Alzheimer's disease: Physiological insights and pathophysiological mechanisms.Journal of cell communication and signaling · 2026Review
- Neuromodulation techniques targeting neurotransmitter dysfunction: Innovation in treatments for Alzheimer's disease.Neural regeneration research · 2026Article
- Targeting the dopaminergic midbrain in Alzheimer's disease: Therapeutic potential of focusing on specific neural circuits rather than single molecular pathways.Neural regeneration research · 2026Article
- Neuromodulation of excitation-inhibition balance in dementia with lewy bodies: a translational framework.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Super-twisting sliding mode control of dopamine release in VTA dopaminergic neuron model: a simulation study.Scientific reports · 2026Article
- Photostimulation of locus coeruleus CA1 catecholaminergic terminals reversed Spatial memory impairment in an alzheimer's disease mouse model.Psychopharmacology · 2026Article
- Deciphering the microenvironment of adult neurogenesis: a perspective from neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Neurotransmitter Systems in Alzheimer's Disease.Current issues in molecular biology · 2026Review
- Alzheimer's Pathology Enhances Excitatory Synaptic Input and Integration in VTA Dopamine Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- The functional minisatellite at the 3'-UTR of SLC6A3/DAT1 and dementia spectrum disorders: an association study in a population of Central Italy.BMC medical genomics · 2026Article
- VTA-forebrain connectivity moderates adaptive behavior.Brain structure & function · 2026Review
- Article
- Dopamine D3 receptor blockade restores hippocampal synaptic plasticity and rescues memory deficits in Alzheimer's disease mouse models.Frontiers in aging neuroscience · 2026Article
- The dopaminergic system in neurodevelopment: preclinical models of neurodevelopmental disorders and susceptibility to neurodegeneration.Frontiers in cellular neuroscience · 2026Review
- Heated Tobacco Products: Emerging Health Outcomes and Insights into Oxidative Stress and Pro-Inflammatory-Driving Mechanisms.Antioxidants (Basel, Switzerland) · 2025Review
- Misclassification in memory modification ineLife · 2025Article
- Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer's Disease.Molecular neurodegeneration · 2025Article
- Optogenetic stimulation of midbrain dopaminergic neurons rescues hippocampal synaptic plasticity deficits in a mouse model of Alzheimer's disease.Translational psychiatry · 2025Article
- PKC-dependent enhancement of glutamate input to VTA dopamine neurons in 3xTg-AD mice.bioRxiv : the preprint server for biology · 2025Article
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12 authors.
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Abstract
Early and progressive dysfunctions of the dopaminergic system from the Ventral Tegmental Area (VTA) have been described in Alzheimer's Disease (AD). During the long pre-symptomatic phase, alterations in the function of Parvalbumin interneurons (PV-INs) are also observed, resulting in cortical hyperexcitability represented by subclinical epilepsy and aberrant gamma-oscillations. However, it is unknown whether the dopaminergic deficits contribute to brain hyperexcitability in AD. Here, using the Tg2576 mouse model of AD, we prove that reduced hippocampal dopaminergic innervation, due to VTA dopamine neuron degeneration, impairs PV-IN firing and gamma-waves, weakens the inhibition of pyramidal neurons and induces hippocampal hyperexcitability via lower D2-receptor-mediated activation of the CREB-pathway. These alterations coincide with reduced PV-IN numbers and Perineuronal Net density. Importantly, L-DOPA and the selective D2-receptor agonist quinpirole rescue p-CREB levels and improve the PV-IN-mediated inhibition, thus reducing hyperexcitability. Moreover, similarly to quinpirole, sumanirole - another D2-receptor agonist and a known anticonvulsant - not only increases p-CREB levels in PV-INs but also restores gamma-oscillations in Tg2576 mice. Conversely, blocking the dopaminergic transmission with sulpiride (a D2-like receptor antagonist) in WT mice reduces p-CREB levels in PV-INs, mimicking what occurs in Tg2576. Overall, these findings support the hypothesis that the VTA dopaminergic system integrity plays a key role in hippocampal PV-IN function and survival, disclosing a relevant contribution of the reduced dopaminergic tone to aberrant gamma-waves, hippocampal hyperexcitability and epileptiform activity in early AD.
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