Abstract
Despite negative association in cognition and memory, mice harboring Val66Met BDNF SNP (BDNFM/M)
exhibit enhanced motor recovery accompanied by elevated excitatory
synaptic markers VGLUT1 and VGLUT2 in striatum contralateral to
unilateral ischemic stroke. The cortico-striatal pathway is a critical
gateway for plasticity of motor/gait function. We hypothesized that
enhanced excitability of the cortico-striatal pathway, especially of the
contralateral hemisphere, underlies improved motor recovery. To test
this hypothesis, we examined the key molecules involving excitatory
synaptogenesis: Thrombospondins (TSP1/2) and their neuronal receptor
α2δ-1. In WT brains, stroke induced expressions of TSP1/2-mRNA. The
contralateral hemisphere of BDNFM/M mice showed heightened
TSP2 and α2δ-1 mRNA and protein specifically at 6 months post-stroke.
Immunoreactivities of TSPs and α2δ-1 were increased in cortical layers
1/2 of stroked BDNFM/M animals compared with BDNFM/M
sham brains at this time. Areal densities of excitatory synapses in
cortical layer 1 and striatum were also increased in stroked BDNFM/M
brains, relative to stroked WT brains. Notably, the frequency of
GABAergic synapses was greatly reduced along distal dendrites in
cortical layer 1 in BDNFM/M brains, whether or not stroked,
compared with WT brains. There was no effect of genotype or treatment on
the density of GABAergic synapses onto striatal medium spiny neurons.
The study identified molecular and synaptic substrates in the
contralateral hemisphere of BDNFM/M mice, especially in
cortical layers 1/2, which indicates selective region-related synaptic
plasticity. The study suggests that an increase in
excitatory-to-inhibitory synaptic balance along the contralateral
cortico-striatal pathway underlies the enhanced functional recovery of
BDNFM/M mice.
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