title: High frequency stimulation alters motor maps, impairs skilled reaching performance and is accompanied by an upregulation of specific GABA, glutamate and NMDA receptor subunits.
abstract: High frequency stimulation (HFS) has the potential to interfere with learning and memory. HFS and motor skill training both lead to potentiation of the stimulated network and alter motor map expression. However, the extent to which HFS can interfere with the learning and performance of a skilled motor task and the resulting effect on the representation of movement has not been examined. Moreover, the molecular mechanisms associated with HFS and skilled motor training on the motor cortex are not known. We hypothesized that HFS would impair performance on a skilled reaching task, and would be associated with alterations in motor map expression and protein levels compared to non-stimulated and untrained controls. Long Evans Hooded rats were chronically implanted with stimulating and recording electrodes in the corpus callosum and frontal neocortex, respectively. High frequency theta burst stimulation or sham stimulation was applied once daily for 20 sessions. The rats were divided into five groups: control, HFS and assessed at 1 week post stimulation, HFS and assessed 3 weeks post stimulation, reach trained, and HFS and reach trained. A subset of rats from each group was assessed with either intracortical microstimulation (ICMS) to examine motor map expression or Western blot techniques to determine protein expression of several excitatory and inhibitory receptor subunits. Firstly, we found that HFS resulted in larger and reorganized motor maps, and lower movement thresholds compared to controls. This was associated with an up-regulation of the GABA(A)α1 and NR1 receptor subunits 3 weeks after the last stimulation session only. Stimulation affected skilled reaching performance in a subset of all stimulated rats. Rats that were poor performers had larger rostral forelimb areas, higher proximal and lower distal movement thresholds compared to rats that were good performers after stimulation. Reach training alone was associated with an up-regulation of GABA(A)α1, α2, GluR2, NR1 and NR2A compared to controls. HFS and reach-trained rats showed an up-regulation of GABA(A)α2 compared to stimulated rats that were not reach-trained. Therefore, we have shown that HFS induces significant plasticity in the motor cortex, and has the potential to disrupt performance on a skilled motor task.
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: A K
authors.initials: AK
authors.lastname: Henderson
authors.forename: Q J
authors.initials: QJ
authors.lastname: Pittman
authors.forename: G C
authors.initials: GC
authors.lastname: Teskey
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001696:Biomechanical Phenomena; D055592:Biophysical Phenomena; D001931:Brain Mapping; D004558:Electric Stimulation / Q000009:adverse effects*; D004567:Electrodes, Implanted; D005552:Forelimb / Q000502:physiology; D008297:Male; D009044:Motor Cortex / Q000502:physiology; D019957:Motor Skills Disorders / Q000209:etiology*; D009068:Movement / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D021122:Protein Subunits; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; C104722:glutamate receptor ionotropic, AMPA 2