Abstract Details

Title Superior Motor Performance Associated Behavioral, Physiological, and Biochemical Changes in Mice with a Rif1I107T/I107T Mutation

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) S25 - Emerging Stroke Therapies and Risk Stratification (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

Objective Investigation of the motor super-performance conferring downstream mechanisms in mice with a Rif1^I107T/I107T mutation.

Background Although motor impairment represents a common phenotype in many neurological disorders, treatment options for motor recovery remain limited. Using a previously identified gain-of-function mutation (Rif1^I107T/I107T, Jakkamsetti et. al., J. Physiology 2024) linked to superior motor performance, we employed a top-down approach, spanning behavior, function, and molecular mechanisms, to uncover targetable pathways underlying motor control.

Design/Methods Mice with a CRISPR-induced Rif1^I107T/I107T mutation prior identified via a forward genetics rotarod motor screen and their littermate controls were assayed for other motor and non-motor behaviors. In vivo anesthetized recordings were obtained from cerebellar purkinje single-units in lobule IV-V. RNA-seq and immunohistochemistry assays were done for forebrain, cerebellum and spinal cord. Further cerebellar work included qPCR and western blot assays. Photothrombotic stroke was induced under anesthesia on the right side, 1.7 mm lateral to bregma in the putative forelimb representation.

Results Rif1^I107T/I107T enhanced performance that extended to other motor but not non-motor behaviors. Cerebellum purkinje cells showed more regular firing and diminished oscillation frequencies associated with recurrent inhibition. Rif1^I107T/I107T enhanced binding to guanosine-rich G-quadruplex (G4) RNA structures. While forebrain and spinal cord RNA expression did not change, for cerebellar RNAs with higher expression in Rif1^I107T/I107T mice, more had G4 structures, and gene enrichment assays showed strong association with motor coordination, cerebellar lobule IV-V, synaptic transmission, and serine-threonine kinase activity. Among these RNAs, Nab2, Kif5c and Kcnma1 satisfied the criteria of possible downstream effectors and showed increased cerebellar expression in Rif1^I107T/I107T mice. Increasing lobule IV-V expression of Nab2 in wild-type mice conferred temporary superior motor performance. Rif1^I107T/I107T mice recovered faster and to a greater extent after cortical photothrombotic stroke.

Conclusions

Our findings reveal a mouse Rif1^I107T/I107T mutation induced novel, potentially modulable pathway relevant to superior motor behavior and possible stroke treatment.

Authors/Disclosures
Vikram Jakkamsetti, MD, MBBS, PhD (UT Southwestern Medical Center) PRESENTER	Dr. Jakkamsetti has received research support from National Institute of Health.
Qian Ma, PhD	Dr. Ma has nothing to disclose.
Gustavo Angulo	Mr. Angulo has nothing to disclose.
Dan Chen, MD, PhD	Dr. Chen has received personal compensation for serving as an employee of Axsome. Dr. Chen has stock in Axsome.
Tigwa Davis, PhD	Dr. Davis has received personal compensation for serving as an employee of Inovalon.
Juan Pascual, MD, PhD	The institution of Dr. Pascual has received research support from NIH.

��ɫ��

��ɫ��