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Sex differences in α4βδ GABAA receptor-regulated synaptic pruning in the primary motor cortex during adolescence and its role in motor learning flexibility
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Smith, Sheryl
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Spring 2025
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2025-03-17
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Michael Tekin Thesis.pdf
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Background: Both human and mouse studies report sex differences in motor learning flexibility.
While males are capable of motor learning, after puberty, reports suggest that they struggle with
behavioral flexibility in motor learning compared to females. α4βδ GABAA receptor (GABAR)
regulated adolescent synaptic pruning of mushroom spines in CA1 hippocampus has been shown
to be necessary for learning flexibility of spatial tasks. I believe this deficit in motor learning
flexibility is caused by the spatial limitations and higher energy cost caused by increased
dendritic spine density in our α4 -/- mice. Since learning of motor skills causes an initial increase
in dendritic spines in the primary motor cortex (M1), I predicted that differences in α4βδ
GABAR triggered mushroom spine pruning M1 would play a role in this sex difference.
However,, the role that motor activity would have on adolescent synaptic pruning in M1 is
unclear. While running wheel activity is reported to increase spines in M1, it is unclear how
motor activity will interact with adolescent synaptic pruning of mushroom spines in this area or
its afferent input from prelimbic prefrontal cortex (PL PFC) which also undergoes pruning.
Methods: I measured the mushroom spine density in the basilar dendrites of layer (L) 5 M1 pyramidal cells in pubertal and post-pubertal C57Bl/6J mice of both sexes to determine if there
was a sex difference in mushroom spine pruning. If male and/or female mice exhibited
mushroom spine pruning, I measured mushroom spine density in α4 -/- mice of the
corresponding sex to determine if α4βδ GABAR played a role in this process. To assess the
effects motor activity had on adolescent synaptic pruning, I exposed all groups that experienced
this process to a voluntary running wheel during puberty and measured mushroom spine density.
To assess motor learning flexibility in relevant groups I taught mice how to perform a constant speed rotarod test initially (“learning”) and assessed performance on an accelerating speed
rotarod test the following day (“learning flexibility”).
Results: Only female wild-type mice exhibited synaptic pruning of mushroom spines in the
proximal region of basilar dendrites of L5 M1 pyramidal cells (>60% pubertal: 2.23 ± 0.21
spines/10 μm; post-pubertal: 0.81 ± 0.14 spines/10 μm, P < 0.001). Mushroom spine density of
the distal dendrites was unchanged for both sexes. This decrease in mushroom spines was not
observed in female α4 -/- mice, implicating α4βδ GABARs as the mechanism. Pubertal
expression of α4 was greater in female M1, a likely reason for the sex difference in pruning.
Motor activity offset pruning in female L5 M1 (control mice: 0.98±0.40 spines/10μm, running
wheel mice:1.87±0.77 spines/10μm, P = 0.0405) and increased mushroom spines in L5 PL PFC
(control mice: 0.79±0.37 spines/10μm, running wheel mice: 1.41±0.45 spines/10μm, P =
0.0140). The mushroom spine pruning of female wild-type M1 was associated with improved
motor learning flexibility compared to the groups with no pruning (male wild-type, female α4 -/) on the accelerating speed rotarod test (P = 0.006).
Discussion: My results demonstrate sex differences in adolescent synaptic pruning
corresponding with sex differences in motor learning flexibility. Adolescent synaptic pruning
was triggered by the α4βδ GABARs which emerge at puberty. This process appears to be offset
by motor activity in M1 and PL PFC but the implications of this on motor learning flexibility are
unclear. Studying synaptic pruning has important implications in the application of drugs that
target pruning of mushroom spine pruning because sub populations of people with autism
spectrum disorder have a functional knockdown of the α4βδ GABAR and impaired behavioral
flexibility.
Citation
Tekin, M. (2025). Sex differences in α4βδ GABAA receptor-regulated synaptic pruning in the primary motor cortex during adolescence and its role in motor learning flexibility [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/17055