The study investigates the role of dopamine neuron degeneration in the Ventral Tegmental Area (VTA) in causing hippocampal hyperexcitability in an experimental model of Alzheimer's Disease (AD). Using the Tg2576 mouse model, the researchers found that reduced hippocampal dopaminergic innervation due to VTA dopamine neuron degeneration impairs Parvalbumin interneurons (PV-INs) firing and gamma-waves, weakens the inhibition of pyramidal neurons (PNs), and induces hippocampal hyperexcitability. These changes are accompanied by reduced PV-IN numbers and Perineuronal Net density. Treatment with L-DOPA and the selective D2-receptor agonist quinpirole restored p-CREB levels and improved PV-IN-mediated inhibition, reducing hyperexcitability. Similarly, the D2-receptor agonist sumatriptan, known for its anticonvulsant properties, increased p-CREB levels in PV-INs and restored gamma-oscillations. Conversely, blocking dopaminergic transmission with the D2-like receptor antagonist sulpiride reduced p-CREB levels in PV-INs, mimicking the effects of VTA dopamine neuron degeneration. These findings suggest that the integrity of the VTA dopaminergic system is crucial for maintaining PV-IN function and survival, and that reduced dopaminergic tone contributes to aberrant gamma-waves, hippocampal hyperexcitability, and epileptiform activity in early AD.The study investigates the role of dopamine neuron degeneration in the Ventral Tegmental Area (VTA) in causing hippocampal hyperexcitability in an experimental model of Alzheimer's Disease (AD). Using the Tg2576 mouse model, the researchers found that reduced hippocampal dopaminergic innervation due to VTA dopamine neuron degeneration impairs Parvalbumin interneurons (PV-INs) firing and gamma-waves, weakens the inhibition of pyramidal neurons (PNs), and induces hippocampal hyperexcitability. These changes are accompanied by reduced PV-IN numbers and Perineuronal Net density. Treatment with L-DOPA and the selective D2-receptor agonist quinpirole restored p-CREB levels and improved PV-IN-mediated inhibition, reducing hyperexcitability. Similarly, the D2-receptor agonist sumatriptan, known for its anticonvulsant properties, increased p-CREB levels in PV-INs and restored gamma-oscillations. Conversely, blocking dopaminergic transmission with the D2-like receptor antagonist sulpiride reduced p-CREB levels in PV-INs, mimicking the effects of VTA dopamine neuron degeneration. These findings suggest that the integrity of the VTA dopaminergic system is crucial for maintaining PV-IN function and survival, and that reduced dopaminergic tone contributes to aberrant gamma-waves, hippocampal hyperexcitability, and epileptiform activity in early AD.