Targeting mGluR2/3 Signaling With LY341495 Restores Dentate Gyrus Function and Cognitive Performance in a Male Mouse Model of Alzheimer's Disease

  • CNS Neurosci Ther. 2026 May;32(5):e70916. doi: 10.1002/cns.70916.
Cui-Ping Chen  1 ,  Ting Zhang  2 ,  Er-Deng E  2 ,  Tian-Yang Xu  2 ,  Qing Han  1 ,  Xiang Gao  3 ,  Jie Sun  3 ,  Yi Huang  3 ,  Jian-Hong Yang  1 ,  Xiao-Qin Zhang  1  2
Affiliations
  • 1. Cerebrovascular Disease Center, Ningbo Key Laboratory of Nervous System and Brain Function, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
  • 2. Department of Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang, China.
  • 3. Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
PMID: 42138018 DOI: 10.1002/cns.70916
Abstract

Background: Aberrant metabotropic glutamate receptor 2/3 (mGluR2/3) signaling has been implicated in the synaptic and cognitive deficits observed in Alzheimer's disease (AD), yet the underlying regulatory mechanisms remain unclear. This study investigated the therapeutic potential of LY341495, a selective mGluR2/3 antagonist, in APP/PS1 transgenic mice, a widely used AD model.

Methods: Male APP/PS1 mice were treated with the selective mGluR2/3 antagonist LY341495. Cognitive performance was evaluated using behavioral tests. Hippocampal dentate gyrus (DG) alterations were examined by immunohistochemistry and electrophysiology, including analyses of mGluR2/3 expression, excitatory synaptic activity, adult neurogenesis, calbindin expression, and Amyloid-β plaque burden.

Results: APP/PS1 mice exhibited pathological upregulation of mGluR2/3 in the DG, accompanied by altered presynaptic glutamatergic transmission, reduced neurogenesis, decreased calbindin expression, and deficits in recognition and spatial memory. LY341495 treatment attenuated the aberrant mGluR2/3 upregulation, enhanced excitatory synaptic activity, and improved calbindin levels and neurogenesis in the DG. Importantly, these changes were associated with significant reductions in DG Amyloid-β plaque burden and marked improvements in cognitive performance.

Conclusions: This study highlights the novelty of linking mGluR2/3 inhibition to the restoration of calcium-buffering capacity, as reflected by calbindin expression and neurogenesis, processes critical for DG plasticity and resilience. These findings underscore the therapeutic potential of LY341495 as a novel intervention targeting mGluR2/3 signaling in AD.

Keywords
Alzheimer's disease; LY341495; cognitive deficits; dentate gyrus; metabotropic glutamate receptors.
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