2026 ECNP Congress

PS02-2136

Targeted activation of the dorsolateral striatum improves spatial memory performance in a mouse model of alzheimer’s disease

Alessia Frenza — V. Latina, E. Uliva, M.F. Criscuolo, S. Pugliano, A. Mele, G. Amadoro, A. Rinaldi · Sapienza University of Rome, Department of Biology and Biothecnology, Rome, Italy

2026 ECNP Congress

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated Tau (p-Tau) in the hippocampus and cortex, leading to neuroinflammation, impaired neurotransmission and progressive neuronal loss. Preclinical therapeutic strategies have largely focused on stimulating affected brain circuits [1,2], but their efficacy declines as neurodegeneration progresses within these regions. Although cognitive decline represents one of the earliest clinical hallmarks of AD, a subset of patients exhibits a resilient phenotype in the initial stages of the disease [3]. This phenomenon is often attributed to “neural compensation”, whereby relatively spared brain regions increase their activity to support failing functions [4-5]. The dorsolateral striatum (DLS), which appears less vulnerable to AD-related pathology, has not traditionally been associated with spatial memory. Nevertheless, emerging evidence suggests its involvement in long-term spatial memory encoding [6]. Based on this, we tested the hypothesis that targeted activation of the DLS could induce a compensatory response to mitigate spatial memory deficits in preclinical models of AD. Initial molecular characterisation was conducted on 6-month-old male APP23 mice. Western blot analysis of hippocampal tissue revealed marked p-Tau accumulation in APP23 mice compared to WT (p=0.0003;unpaired t-test;N=7 per group) and significant GFAP upregulation, indicating active neuroinflammation (p=0.0054;unpaired t-test;N=4 per group). These molecular alterations correlated with spatial memory impairments in the Morris Water Maze (MWM). To address these deficits, a chemogenetic approach was employed. An adeno-associated virus expressing the excitatory DREADD hM3D(Gq) was bilaterally injected into the DLS. Neuronal activity was enhanced through systemic administration of clozapine-N-oxide (CNO, 3 mg/kg) during the acquisition and consolidation phases of the MWM. All experimental groups successfully learned the platform location during training [WT-Veh(N=9):p=0.0001; WT-CNO(N=7):p=0.0198;APP23-Veh(N=5):p<0.0001;APP23-CNO(N=6):p=0.0004; RM one-way ANOVA]. During the 24-hour probe test, the APP23-CNO group showed a significant improvement in spatial memory, spending more time in the target quadrant compared to the other quadrants, while APP23 mice receiving vehicle did not [WT-Veh(N=9):p=0.0064; WT-CNO(N=7):p=0.0072; APP23-Veh(N=5):p=0.1530; APP23-CNO(N=6):p=0.0010; Target vs. Others;Tukey’s post-hoc). This effect was not maintained at the 14-day probe test [WT-Veh(N=9):p=0.0899; WT-CNO(N=7):p=0.9485; APP23-Veh(N=5):p=0.8704; APP23-CNO(N=6):p=0.0599; Target vs. Others;Tukey’s post-hoc], indicating that DLS stimulation enhances recent (24h) but not remote (14 days) spatial memory in APP23 mice. The same experimental approach was applied to 6-month-old 3xTg-AD mice. In contrast to the APP23 model, this model did not exhibit significant increase in p-Tau levels (p=0.1719;unpaired t-test;N=4 per group) or GFAP expression compared to WT at this age (p=0.8002;unpaired t-test N=3 per group). Consistently, behavioural assessment demonstrated preserved spatial memory both during recent [WT-Veh(N=6):p=0.0003; WT-CNO(N=6):p<0.0001; 3xtg-Veh(N=10):p<0.0001; 3xTg-CNO(N=6):p<0.0001; Target vs. Others;Tukey’s post-hoc] and remote probe tests [WT-Veh(N=6):p=0.1039; WT-CNO(N=6):p=0.0570; 3xTg-Veh(N=10):p=0.0001; 3xTg-CNO(N=6):p=0.0360; Target vs. Others;Tukey’s post-hoc]. Ongoing studies at 9 months of age aim to determine the onset of spatial memory deficits in this model and to evaluate whether DLS stimulation could exert beneficial effects comparable to those observed in APP23 mice. Overall, these findings identify the DLS as a promising substrate for neural compensation, suggesting that enhancing activity in relatively preserved regions can alleviate spatial memory deficits in early-stage AD.

References

  1. Perusini et al. 2017 (DOI: 10.1002/hipo.22756);
  2. Dheeraj et al. 2016 (doi:10.1038/nature17172);
  3. Elman et al. 2014 (doi:10.1038/nn.3806);
  4. Stern, 2009 (https://doi.org/10.1016/j.neuropsychologia.2009.03.004);
  5. Pignataro et al. 2019 (https://doi.org/10.1016/j.biopsych.2018.10.018);
  6. Mastrorilli et al. 2022 (https://doi.org/10.1073/pnas.2120717119)