Altered Forebrain Functional Connectivity and Neurotransmission in a Kinase-Inactive Met Mouse Model of Autism

Abstract

MET, the gene encoding the tyrosine kinase receptor for hepatocyte growth factor, is a susceptibility gene for autism spectrum disorder (ASD). Genetically altered mice with a kinase-inactive Met offer a potential model for understanding neural circuit organization changes in autism. Here, we focus on the somatosensory thalamocortical circuitry because distinct somatosensory sensitivity phenotypes accompany ASD, and this system plays a major role in sensorimotor and social behaviors in mice. We employed resting-state functional magnetic resonance imaging and in vivo high-resolution proton MR spectroscopy to examine neuronal connectivity and neurotransmission of wild-type, heterozygous Met–Emx1, and fully inactive homozygous Met–Emx1 mice. Met–Emx1 brains showed impaired maturation of large-scale somatosensory network connectivity when compared with wild-type controls. Significant sex × genotype interaction in both network features and glutamate/gamma-aminobutyric acid (GABA) balance was observed. Female Met–Emx1 brains showed significant connectivity and glutamate/GABA balance changes in the somatosensory thalamocortical system when compared with wild-type brains. The glutamate/GABA ratio in the thalamus was correlated with the connectivity between the somatosensory cortex and the thalamus in heterozygous Met–Emx1 female brains. The findings support the hypothesis that aberrant functioning of the somatosensory thalamocortical system is at the core of the conspicuous somatosensory behavioral phenotypes observed in Met–Emx1 mice.

Global spatiotemporal synchronizing structures of spontaneous neural activities in different cell types

“…These structures, present in the spontaneous activity of the brain, show a certain level of conservation across different cell types, ages, and even species (humans and mice) 24 , 43 . Although state-dependent FC has been identified in various contexts, the synchronization of global neural activities extends beyond the simple superposition of synchronized or desynchronized states 8 – 14 . FC encompasses a more intricate picture as a highly multidimensional continuum of synchronizations, including a time lag (or traveling waves, which may be initially interpreted as a desynchronized state) and differences between cells 8 .…”

“…Source data are provided as a Source Data file. simple superposition of synchronized or desynchronized states [8][9][10][11][12][13][14] . FC encompasses a more intricate picture as a highly multidimensional continuum of synchronizations, including a time lag (or traveling waves, which may be initially interpreted as a desynchronized state) and differences between cells 8 .…”

“…The spontaneous neural activity of the brain demonstrates selforganized intrinsic dynamics [1][2][3][4][5][6][7] , which are closely associated with stimulation, cognition, and behavior and range from highly synchronized to desynchronized 8 . Functional connectivity (FC) has been commonly employed to depict the spatial organization of brain synchronization and is recognized for its changes during development and across pathological conditions [9][10][11][12][13][14] . However, mounting evidence gathered in various states, including wakefulness, using various techniques ranging from the cellular to the whole-brain large-scale has revealed the widespread presence of nonstationary synchronization [15][16][17][18][19][20][21][22][23][24] .…”

Translational Magnetic Resonance Imaging in Autism Spectrum Disorder From the Mouse Model to Human

“…Engrailed-2 (En2) knockout adult mice, which show a lower expression of FMR1 and anatomical defects common to FMR1 knockout, significantly reduce synchronization in the somatosensory-auditory/associative cortices and the dorsal thalamus ( Chelini et al, 2019 ). Functional connectivity between the somatosensory cortex and the thalamus is significantly reduced in conditionally mutant adult Met-Emx1 mice expressing a kinase-dead Met restricted to the cerebral cortex and the hippocampal structures ( Tang et al, 2019 ). Adult BTBR T + Itpr3tf/J (BTBR) mice, originally bred for studies on insulin resistance, diabetes-induced nephropathy, and phenylketonuria, show a reduction in long-range functional connectivity involving retrosplenial areas and lateral cortical regions ( Sforazzini et al, 2016 ).…”

Control of cortical synapse development and plasticity by MET receptor tyrosine kinase, a genetic risk factor for autism

“…It has been previously reported that in thalamocortical slices prepared from Met cKO mice, the E/I ratio is biased toward excitation due to decreased GABA A receptor-mediated inhibition (Lo, Erzurumlu, & Powell, 2016), an effect that may be due to insulin fails to increase GABA A receptor-mediated response in the barrel cortex of Met cKO mice. Another recent study employed resting-state functional magnetic resonance imaging and in vivo high-resolution proton MR spectroscopy to examine neuronal connectivity (Tang et al, 2019). The study focused on somatosensory thalamocortical circuitry because somatosensory disturbances are frequently reported co-morbid conditions with ASD, and may be responsible for altered sensorimotor gating and for processing the saliency of social behaviors.…”