Functional Deficits and Diffusion Tensor Magnetic Resonance Imaging of the Olfactory and Vision Systems in the Alzheimer’s Disease Model of Aging GluN3A Knockout Mice

Sensory dysfunction, such as olfactory and visual deficits, is a notorious symptom during the progression of Alzheimer’s disease (AD) and related dementia (ADRD). The causal factor/s and structural disruptions underlying the sensory dysfunction in the AD/ADRD brain are not well understood. The NMDA receptor subunit GluN3A (NR3A) negatively regulates the receptor activity to uphold cellular Ca2+ homeostasis. In GluN3A knockout (KO) mice, animals spontaneously develop chronic neurodegenerative excitotoxicity, cognitive decline, and AD-like pathology. Using diffusion tensor imaging (DTI), we examined neuronal network destruction together with sensory dysfunction in the GluN3A KO mouse. Specific attention was given to the selective vulnerability of the olfactory and visual nuclei, white matter injury in regional connections between subcortical centers and the cortex and hippocampus. Compared to age-matched wild-type (WT) controls (male), consistent with our early reports in younger ages, 18-month-old aging/aged GluN3A KO mice (male) suffered significant olfactory, visual and social deficits, accompanied by marked Aβ42 deposition in the brain. Ex vivo MR images of the GluN3A KO and control brains were acquired on the 7T MRI system, using a four-channel mouse array RF coil. High-resolution 3D T2-weighted RARE anatomical and DTI scans were performed. The DTI analysis revealed that GluN3A KO mice developed brain atrophy, involving significant damage in the white and gray matter of the olfactory and visual systems and impaired pathways among the superior colliculus, lateral geniculate nucleus, and the hippocampus and/or the cortex. This investigation disclosed a receptor-mediated neurodegeneration that explains sensory syndromes featured in a sporadic AD mouse model.