Abstract
We previously demonstrated that the Tg2576 mouse model of Alzheimer's Disease (AD) exhibits degeneration of midbrain dopaminergic neurons, resulting in reduced dopamine (DA) outflow in the hippocampus. These impairments temporally coincide with synaptic plasticity deficits at CA3-CA1 synapses. Notably, systemic administration of dopaminergic agents/drugs rescues the hippocampal deficits in Tg2576 mice. However, whether direct stimulation of the remaining midbrain dopaminergic neurons can restore glutamatergic transmission and rescue plasticity dysfunctions in the context of AD remains unexplored. Here, using both 6-hydroxydopamine (6-OHDA) neurotoxic lesion and optogenetic stimulation in C57BL/6N and DATCre/Tg2576 mice, respectively, we demonstrate that midbrain DA is essential for hippocampal High-Frequency Stimulation-induced Long-Term Potentiation (HFS-LTP) in CA3-CA1 synapses. Indeed, lesioning midbrain DA neurons with 6-OHDA abolishes HFS-LTP and impairs novel object recognition memory. Conversely, optogenetic activation of the midbrain-hippocampal dopaminergic pathway in DATCre/Tg2576 mice enhances glutamatergic transmission and rescues plasticity deficits. Our results highlight the phase-specific role of DA in HFS-LTP, since 6-OHDA lesion affects the late but not the early phase, aligning with prior studies on D1/D5 receptor involvement in protein synthesis-dependent plasticity. Furthermore, we provide novel insights into midbrain DA neuron regulation, demonstrating that phasic, but not prolonged, optogenetic stimulation effectively engages DA neuron activity, restoring hippocampal function in Tg2576 mice. Notably, phasic DA release induces "DA-LTP" via D1/D5 receptors, and restores HFS-LTP in CA3-CA1 synapses of AD mice, underscoring a potential compensatory mechanism counteracting plasticity deficits induced by DA neuron degeneration in Tg2576 mice. These findings support targeting the dopaminergic midbrain as a promising strategy for AD treatment, complementing pharmacological and non-invasive neuromodulatory approaches.