Microcephaly with altered cortical layering in GIT1 deficiency revealed by quantitative neuroimaging

Microcephaly with altered cortical layering in GIT1 deficiency revealed by quantitative neuroimaging:



Publication date: Available online 30 September 2020

Source: Magnetic Resonance Imaging

Author(s): Alexandra Badea, Robert Schmalzigaug, Woojoo Kim, Pamela Bonner, Umer Ahmed, G. Allan Johnson, Gary Cofer, Mark Foster, Robert J. Anderson, Cristian Badea, Richard T. Premont




Highlights


•

Micro-CT revealed microcephaly, significant differences in local skull shape and Hounsfield units for GIT1-KO animals relative to WT controls.•

MRI and deformation based morphometry supported microcephaly findings, and identified main drivers for brain atrophy.•

Mice lacking GIT1 have white matter and cortical layering defects.•

GIT1 has a critical but not uniform role in brain development, pointing to aberrant connectivity.•

High resolution MRI distinguishes cortical layers in GIT1-KO mice and WT controls.



Abstract


G Protein-Coupled Receptor Kinase-Interacting Protein-1 (GIT1) regulates neuronal functions, including cell and axon migration and synapse formation and maintenance, and GIT1 knockout (KO) mice exhibit learning and memory deficits. We noted that male and female GIT1-KO mice exhibit neuroimaging phenotypes including microcephaly, and altered cortical layering, with a decrease in neuron density in cortical layer V. Micro-CT and magnetic resonance microscopy (MRM) were used to identify morphometric phenotypes for the skulls and throughout the GIT1-KO brains. High field MRM of actively-stained mouse brains from GIT1-KO and wild type (WT) controls (n = 6 per group) allowed segmenting 37 regions, based on co-registration to the Waxholm Space atlas. Overall brain size in GIT1-KO mice was ~32% smaller compared to WT controls. After correcting for brain size, several regions were significantly different in GIT1-KO mice relative to WT, including the gray matter of the ventral thalamic nuclei and the rest of the thalamus, the inferior colliculus, and pontine nuclei. GIT1-KO mice had reduced volume of white matter tracts, most notably in the anterior commissure (~26% smaller), but also in the cerebral peduncle, fornix, and spinal trigeminal tract. On the other hand, the basal ganglia appeared enlarged in GIT1-KO mice, including the globus pallidus, caudate putamen, and particularly the accumbens - supporting a possible vulnerability to addiction. Volume based morphometry based on high-resolution MRM (21.5 μm isotropic voxels) was effective in detecting overall, and local differences in brain volumes in GIT1-KO mice, including in white matter tracts. The reduced relative volume of specific brain regions suggests a critical, but not uniform, role for GIT1 in brain development, conducive to brain microcephaly, and aberrant connectivity.

Graphical abstract



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Keywords
Magnetic resonance microscopy
Micro-CT
G protein-coupled receptor kinase-interacting Protein-1 (GIT1)
Morphometry
Shape analysis
Volume covariance
Brain networks