AMPA RECEPTOR DENSITY DETERMINES LOCAL AND GLOBAL FUNCTIONAL CONNECTIVITY
Authors: Yatomi *Taisuke Yatomi , Tomasi Dardo , Tsugawa Sakiko , Tani Hideaki , Koizumi Teruki , Nagai Nobuhiro , Nakajima Shinichiro , Ohtani Yohei , Nomoto-Takahashi Kie , Nakajima Waki , Hatano Mai , Uchida Hiroyuki , Takahashi Takuya 
Published: February 2025

Abstract

Background
Functional connectivity density, both local (lFCD) and global (gFCD), derived from functional magnetic resonance imaging (fMRI) delineates the prominence of regional and widespread connectivity hubs throughout the brain. However, it remains unknown regarding the neurobiological mechanism of the hubness of lFCD and gFCD. α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulates most of excitatory signals as a main controller of activities relating to excitatory signals in the brain. We hypothesized that there was a positive association between AMPA- receptor density and both lFCD and gFCD-lFCD.

Objectives
The aim of this study is to investigate the relationship between AMPA receptor density and the local and global hubness in the whole brain.

Methods
We examined the association between AMPA receptor density, measured with [11C]K-2 PET (positron emission tomography), and lFCD and gFCD (using gFCD-lFCD as gFCD as follows) of the whole functional connectivities in 31 healthy subjects. rsfMRI (resting-state functional MRI) data were processed to extract lFCD and gFCD values across the whole brain, encompassing Yeo’ s 7 network Atlas areas and the 83 region of interests within the Hammers-Smith Atlas. Subsequently, in each region of these ROIs (region of interests) or networks, the voxel-wise SUVR (standard uptake value ratio in AMPA- receptor PET, using white matter as a reference region)-lFCD and SUVR-gFCD correlations were ascertained. Furthermore, we assessed the link between the absolute magnitudes of lFCD/gFCD and their respective SUVR correlations within each Hammers-Smith Atlas domain. All correlational evaluations utilized Spearman's rank correlation coefficient.

Results
Our findings revealed that both lFCD and gFCD exhibited mediate to strong positive associations with AMPA receptor density with AMPA receptor density in nearly all regions of interests and networks, notably within the anterior cingulate cortex and the default mode network. In particular, the average lFCD correlation coefficients were 0.46 in the whole brain, 0.54 in the Default Mode Network (DMN), and 0.56 in the Visual Network (VN), 0.84 in the anterior cingulate gyrus (ACC), respectively. The mean gFCD correlation coefficients of the healthy subjects were 0.46 in the whole brain, 0.52 in the DMN, 0.54 in the VN, 0.84 in the anterior cingulate gyrus. Moreover, the coefficient of SUVR-lFCD correlation was positively correlated with the value of lFCD (r=0.23, p=0.033), though that of SUVR-gFCD correlation was not correlated with the value of gFCD (r=-0.0064, p=0.95).

Conclusion
Our research underscores the integral role of postsynaptic AMPA receptor signaling in facilitating both proximate and widespread functional communication throughout the brain. This influence is especially pronounced in regions recognized as pivotal network hubs. Especially, the higher lFCD of the ROI was, the more AMPA receptor density regulates that lFCD.

References
1.Miyazaki, T. et al. Visualization of AMPA receptors in living human brain with positron emission tomography. Nat. Med. 26, 281–288. https://doi.org/10.1038/s41591-019-0723-9 (2020).
2.Tomasi, D et al. Functional Connectivity Density Mapping. Proc. Natl. Acad. Sci. U. S. A. 107(21), 9885- 9890. https://www.pnas.org/doi/abs/10.1073/pnas.1001414107 (2010).