Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer's disease

• Published in: Neurobiology of disease Vol. 116; pp. 142 - 154
• Main Authors: Cordella, Alberto, Krashia, Paraskevi, Nobili, Annalisa, Pignataro, Annabella, La Barbera, Livia, Viscomi, Maria Teresa, Valzania, Alessandro, Keller, Flavio, Ammassari-Teule, Martine, Mercuri, Nicola Biagio, Berretta, Nicola, D'Amelio, Marcello
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2018; Elsevier
• Subjects: Alzheimer; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Animals; Dopamine; Dopamine - genetics; Dopamine - metabolism; Dopaminergic Neurons - metabolism; DREADD; Excitatory Postsynaptic Potentials - physiology; Hippocampus; Hippocampus - metabolism; l-DOPA; Male; Memory; Mice; Mice, Transgenic; Nucleus accumbens; Nucleus Accumbens - metabolism; Organ Culture Techniques; Subiculum; Synaptic Transmission - physiology; Tg2576; VTA; DAergic; VTA; CNO; Memory; DREADD; LTP; preSub; Cm; Alzheimer; NAc; CaMKIIα; PPR; ANOVA; l-DOPA; Rm; WT; AD; Dopamine; MS; sEPSCs; IEI; AP; Tg2576; Nucleus accumbens; RMP; TH; AAV; aCSF; mEPSCs; Subiculum; FB; DA; Hippocampus
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2018.05.006

The functional loop involving the ventral tegmental area (VTA), dorsal hippocampus and nucleus accumbens (NAc) plays a pivotal role in the formation of spatial memory and persistent memory traces. In particular, the dopaminergic innervation from the VTA to the hippocampus is critical for hippocampal-related memory function and alterations in the midbrain dopaminergic system are frequently reported in Alzheimer's disease (AD), contributing to age-related decline in memory and non-cognitive functions. However, much less is known about the hippocampus-NAc connectivity in AD. Here, we evaluated the functioning of the hippocampus-to-NAc core connectivity in the Tg2576 mouse model of AD that shows a selective and progressive degeneration of VTA dopaminergic neurons. We show that reduced dopaminergic innervation in the Tg2576 hippocampus results in reduced synaptic plasticity and excitability of dorsal subiculum pyramidal neurons. Importantly, the glutamatergic transmission from the hippocampus to the NAc core is also impaired. Chemogenetic depolarisation of Tg2576 subicular pyramidal neurons with an excitatory Designer Receptor Exclusively Activated by Designer Drugs, or systemic administration of the DA precursor levodopa, can both rescue the deficits in Tg2576 mice. Our data suggest that the dopaminergic signalling in the hippocampus is essential for the proper functioning of the hippocampus-NAc excitatory synaptic transmission. •The VTA-hippocampus-NAc loop is pivotal for memory formation.•AD-like Tg2576 mice show low dopaminergic innervation in hippocampus and subiculum.•Tg2576 subicular pyramidal neurons show reduced excitability and impaired LTP.•Tg2576 mice show impaired glutamatergic transmission from subiculum to NAc core.•l-DOPA administration in-vivo rescues all these deficits in Tg2576 mice.