Interhemispheric plasticity is mediated by maximal potentiation of callosal inputs

Abstract

Central or peripheral injury causes reorganization of the brain's connections and functions. A striking change observed after unilateral stroke or amputation is a recruitment of bilateral cortical responses to sensation or movement of the unaffected peripheral area. The mechanisms underlying this phenomenon are described in a mouse model of unilateral whisker deprivation. Stimulation of intact whiskers yields a bilateral blood-oxygen-level-dependent fMRI response in somatosensory barrel cortex. Whole-cell electrophysiology demonstrated that the intact barrel cortex selectively strengthens callosal synapses to layer 5 neurons in the deprived cortex. These synapses have larger AMPA receptor- and NMDA receptor-mediated events. These factors contribute to a maximally potentiated callosal synapse. This potentiation occludes long-term potentiation, which could be rescued, to some extent, with prior long-term depression induction. Excitability and excitation/inhibition balance were altered in a manner consistent with cell-specific callosal changes and support a shift in the overall state of the cortex. This is a demonstration of a cell-specific, synaptic mechanism underlying interhemispheric cortical reorganization.

Keywords: corpus callosum; cortical circuit; interhemispheric plasticity.

Fig. 1.

Bilateral S1BC BOLD fMRI response to intact whisker stimulation. (A) Experimental setup. (B) Representative activation maps (Top Left). Bar graph depicts the average response amplitudes (Right); error bars are SEM; * denotes statistical significance. n, number of animals. Incidence maps depict the likelihood of each voxel’s response (Bottom Left). (C) Representative traces. (D) Representative axial images of sham and ION transection mice. NC, nasal cavity; W, whisker pad; yellow arrows delineate ION; note the black space on ION transection animal (red arrows).

Fig. 2.

Callosal projections from intact to deprived S1BC produce larger AMPAR-mediated events to L5 neurons after unilateral whisker deprivation. (A) Experimental design; asterisk is ChR2 injection site (green). (B) No change in light-evoked Sr-mEPSC amplitudes from intact to deprived L2/3. (C) Sr-mEPSCs are significantly larger to L5. (D) No change between local L5 to L5 electrically evoked Sr-mEPSC amplitudes. Average (Center) and representative (Right) traces are displayed in B−D. Bar graphs represent mean; error bars are SEM; * denotes statistical significance. n, number of cells.

Fig. 3.

NMDAR activity increases to match AMPAR in callosally targeted deprived L5 neurons, and indicates an increase in ifenprodil sensitivity. (A) Biocytin filled L5 principal neuron surrounded by callosal ChR2-YFP expressing terminals (Left); experimental schematic (Right). (B) No change in AMPAR/NMDAR ratio from intact to L5 neurons in deprived S1BC. (C) Deprived L5 neurons display increased ifenprodil sensitivity. Bar graphs represent mean; error bars are SEM; * denotes statistical significance. n, number of cells.

Fig. 4.

Changes in spontaneous activity are restricted to sEPSCs in deprived L5 neurons. (A and B) The sEPSC and sIPSC amplitudes and frequency are not significantly altered in L2/3 (Left and Center); average traces (Right). (C) The sEPSC frequency is unchanged, but amplitude is larger in deprived L5 neurons. (D) The changes in sEPSC amplitude are not multiplicative. (E) The sIPSC frequency and amplitude are unchanged between groups. Bar graphs represent mean; error bars are SEM. n, number of cells.

Fig. 5.

Intrinsic properties of deprived L5 neurons demonstrate an increase in excitability; no change is detected in L2/3. Deprived L2/3 neurons have similar (A) Vm, (B) input resistance, and (C) rheobase values. (D) Representative traces. Deprived L5 neurons have (E) a higher Vm, (F) no change in input resistance, and (G) a lower rheobase value. (H) Representative traces. Bar graphs represent mean; error bars are SEM; * denotes statistical significance. n, number of cells.

Fig. 6.

Unilateral ION occludes callosal LTP from intact to deprived S1BC. LTD is similar between groups. (A) Robust callosal LTP to L5 neurons in sham is elicited; there is no LTP in deprived S1BC. (B) Multiple rounds of LTP induction produce progressively larger potentiation in sham, but deprived L5 neurons do not achieve LTP after multiple inductions. (C) LTD levels were equal between groups. (D) Multiple LTD inductions produced equal magnitudes between groups. (E) LTD induction before LTP protocol elicited LTP in the sham animals; deprived L5 LTP is rescued along the CC. Box plots represent mean; middle line is the median; error bars are minimum and maximum values; * denotes statistical significance.