Overexpression of Astroglial Major Histocompatibility Complex Class I in the Medial Prefrontal Cortex Impairs Visual Discrimination Learning in Mice

Abstract

Background Immune molecules, such as cytokines, complement, and major histocompatibility complex (MHC) proteins, in the central nervous system are often associated with neuropsychiatric disorders. Neuronal MHC class I (MHCI), such as H-2D, regulate neurite outgrowth, the establishment and function of cortical connections, and activity-dependent refinement in mice. We previously established mice expressing MHCI specifically in astrocytes of the media prefrontal cortex (mPFC) using the adeno-associated virus (AAV) vector under the control of the glial fibrillary acidic protein (GFAP) promoter. Mice expressing the soluble form of H-2D (sH-2D) in the mPFC (sH-2D-expressing mice) showed abnormal behaviors, including social interaction deficits and cognitive dysfunctions. However, the pathophysiological significance of astroglial MHCI on higher brain functions remains unclear. Therefore, cognitive function in mice expressing sH-2D in astrocytes of the mPFC was tested using the visual discrimination (VD) task to assess the impact of the astrocyte pathology and resulting behavioral changes.Methods Three separate batches of mice were used in the present study. sH-2D-expressing mice were subjected to the VD and reversal learning tasks, morphological analyses, and pharmacological intervention using clozapine in the social interaction and novel object recognition tasks.Results In pretraining, the performance of sH-2D-expressing mice was normal in response phase sessions (stages 1–4), but impaired in the punish phase session (stage 5). The total numbers of sessions, trials, normal trials, and correction trials to reach the VD criterion were significantly higher in sH-2D-expressing mice than in control mice. A morphological study showed that dendritic complexity was significantly reduced in the dorsal striatum of sH-2D-expressing mice. A treatment with clozapine ameliorated decreased social behavior as well as impaired object recognition memory in sH-2D-expressing mice.Conclusion Collectively, the present results suggest that the overexpression of astroglial MHCI in the mPFC results in impaired VD learning, which may be accompanied by decreased dendritic complexity in the dorsal striatum and mPFC.

Visual discrimination and inhibitory control deficits in mouse models of Down syndrome: A pilot study using rodent touchscreen technology

“…Similar delays were observed in mice that overexpressed a soluble form of the major histocompatibility complex I H‐2D (sH‐2D) in the medial prefrontal cortex through an adeno‐associated virus (AAV). These mice performed normally in early pre‐training stages (Stages 2–4) but showed significant impairment in late pretraining (Stage 5) (Wulaer et al, 2020).…”

“…Similar delays were observed in mice that overexpressed a soluble form of the major histocompatibility complex I H-2D (sH-2D)in the medial prefrontal cortex through an adeno-associated virus (AAV). These mice performed normally in early pre-training stages (Stages 2-4) but showed significant impairment in late pretraining (Stage 5)(Wulaer et al, 2020).Although Dp(16)1/Yey and Ts1Cje mice and their WT littermates were able to complete early pre-training, not all of them were able to successfully move to VD after increasing the task difficulty and introducing an incorrect response during Stage 5.4.3 | Deficits in the Dp(16)1/Yey and Ts1Cje during the VD taskBoth the Dp(16)1/Yey and Ts1Cje mice showed significant deficits in their VD performance versus WT littermates without differences in the average number of trials performed by each genotype. It is worth noting that the Dp(16)1/Yey exhibited more severe learning deficits than the Ts1Cje strain compared to their WT littermates.…”

High salt induces cognitive impairment via the angiotensin II-AT1 and prostaglandin E2-EP1 systems

“…Golgi staining was performed using the FD Rapid Golgi Stain Kit, according to the manufacturer’s protocol (FD NeuroTechnologies, Ellicott City, MD, USA) and a previous report (Wulaer, Hada et al, 2020). The mice were sacrificed by decapitation.…”