Overexpression of TIAM2S, a Critical Regulator for the Hippocampal-Medial Prefrontal Cortex Network, Progresses Age-Related Spatial Memory Impairment

TIAM Rac1-associated GEF 2 short-form protein (TIAM2S) is abundant in specific brain tissues, especially in the hippocampus, a brain region critical for processing and consolidation of spatial memory. However, how TIAM2S plasticizes the microstructure and circuits of the hippocampus to shape spatial memory as a neuroplastic regulator during aging remains to be determined. In this study, transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) were included, and interdisciplinary approaches, such as spatial memory tests and multiparametric magnetic resonance imaging sequences, were conducted to determine the role and the mechanism of TIAM2S in age-related spatial memory deficits. Despite no changes in their neural and glial markers and neuropathological hallmark expression of the hippocampus, behavioral tests showed that the TIAM2S-TG mice, and not wild-type (WT) mice, developed spatial memory impairment at 18 months old. The T2-weighted and diffusion tensor image analyses were performed to further study the possible role of TIAM2S overexpression in altering the hippocampal structure or neuronal circlets of the mice, increasing their vulnerability to developing spatial memory deficits during aging. The results revealed that the 12-month-old TIAM2S-TG mice had hippocampal dysplasticity, with larger volume, increased fiber numbers, and changed mean fractional anisotropy compared to those in the age-matched WT mice. The fiber tractography analysis exhibited significantly attenuated structural connectivity between the hippocampus and medial prefrontal cortex in the TIAM2S-TG mice. In conclusion, overexpression of TIAM2S, a detrimental factor affecting hippocampus plasticity, causes attenuation of the connectivity within hippocampus-mPFC circuits, leading to age-related spatial memory impairment. Graphical Abstract