Dopamine neuron degeneration in the Ventral Tegmental Area causes hippocampal hyperexcitability in experimental Alzheimer’s Disease

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.

Clarifying the role of D1 receptor signalling in Alzheimer's‐related epilepsy commentary on Szabo et al. (2024)

“…In vivo, the sub-chronic treatment of L-DOPA ameliorates hippocampal hyperexcitability by reducing the amplitude of PSs (as proved also by a recent work ;Spoleti et al, 2024); likewise, stimulation of the VTA was found to decrease epileptic activity in hippocampus-kindled mice (Ahmadi et al, 2024).…”

Polycatechols inhibit ferroptosis and modulate tau liquid–liquid phase separation to mitigate Alzheimer's disease

“…35 In the AD brain, Ab plaques were identified to induce dopaminergic degeneration in the ventral tegmental area (VTA). 36 Interestingly, dopamine treatment was found to restore synaptic plasticity and memory cognition in the AD model. Mechanistically, studies have shown that dopamine, and L-Dopa, not only inhibit Ab aggregation but also dissolve the preformed aggregates.…”

Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence

“…Besides GABAergic and glutamatergic synapses [20,28,40], other types of synapses have not been shown, to our best knowledge, to populate PNN meshes. Hippocampal PV+ interneurons receive dopaminergic innervation from ventral tegmental area (VTA) and the firing rate was reduced significantly in those neurons upon VTA dopamine neuron degeneration in the TG2576 mouse model of AD [161]. Futhermore, cortical PV+ interneurons exhibit an abnormal PNN structure, altered action potentials, and deficits in dopaminergic modulation in mice carrying a truncated allele disrupted in schizophrenia allele [162].…”