Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is an important signaling molecule that plays a crucial role in the proper development and function of the central nervous system. A variety of studies have suggested BDNF meets the criteria necessary to modulate cortical reorganization, including a study that found its transcription and release to be activity-dependent. Horizontal synapses in the primary somatosensory area, S1, facilitate functional reorganization across topographical representations. However, the molecular contributors to reorganization are not known. Since BDNF is a known modulator of synaptic transmission, this dissertation focuses on the effects of BDNF on horizontal synapses in S1, hypothesizing that BDNF has the capacity to alter synaptic transmission at these synapses.

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In chapter 1, we found that acute bath application of BDNF had an inhibitory effect on layer II/III local field potentials. The inhibitory effect of BDNF was found to be Trk dependent, as inhibiting protein kinase activity proved to prevent BDNF-dependent inhibition. The mechanism of inhibition shown by BDNF is likely to be similar to a long- term depression (LTD) -like mechanism, because inducing LTD prior to BDNF exposure occluded the BDNF effect, and BDNF exposure prior to LTD induction occluded the LTD effect. The LTD that occluded the BDNF effect was shown to be non-N-methyl-D- aspartic acid receptor (NMDAR) dependent, as it was unaffected by application of an NMDAR antagonist.

In chapter 2, we continued to investigate the inhibitory effect of BDNF by exploring the mechanism by which the LFP was reduced. Using a whole-cell patch clamp technique, we found that BDNF reduces the excitatory post synaptic current, EPSC, of both NCB and CB populations without changing the inhibitory post synaptic current, ISPC. BDNF was also found to reduce excitability by significantly increasing rheobase, the amount of current required to elicit a single action potential. Stimulating trains of action potentials resulted in BDNF-exposed cells having a reduction in the amount of action potentials they produced. All together, these findings support BDNF acting to inhibit excitation in these populations of cells. This inhibition by BDNF could be necessary in supporting the synaptic plasticity that is prompted during reorganization.

Cortical sensory maps are highly organized structures that contain point-to-point representations of sensory inputs. This organization emerges in-part from horizontal connections that limit activity-flow across representational borders (local-circuit constraint properties). Interestingly, this organization undergoes experience-dependent modifications throughout life. This dissertation examines changes in local-circuit constraint properties during cortical reorganization.

Synaptic plasticity of horizontal connections could modify activity-flow across borders. Very little is known about inhibitory synaptic plasticity, its relationship to excitatory synaptic plasticity, and their relationship to functional organization. To investigate this, we located the forepaw/lower jaw (FP/LJ) of the primary somatosensory cortex (SI) in vivo, and used whole cell-patch electrophysiology to record excitatory and inhibitory responses of horizontal connections in vitro. Connections that remained within the representation (continuous) and those that crossed from one representation to another (discontinuous) were both examined before and after tetanization, allowing us to examine differences associated with borders. Tetanic stimulation induced diverse forms of synaptic plasticity, with long-term potentiation (LTP) dominating for excitation and long-term depression dominating for inhibition. The border did not restrict this plasticity in either case. In contrast, tetanization elicited LTP of monosynaptic inhibitory responses in continuous, but not discontinuous connections. These results demonstrate that continuous and discontinuous horizontal connections are capable of diverse plasticity responses that could theoretically functionally reorganize the cortex.

Axon remodeling could also change activity-flow across borders. To investigate this, we examined axon remodeling during long-durations of reorganization. We located the FP/LJ border and then iontophoresed a retrograde axonal tracer near the border at different durations of forelimb-denervation or sham-denervation. In sham-denervated animals, neurons close to the border had axonal projections oriented away from the border (axonal bias). Forelimb denervation resulted in a sustained change in border location and a significant reduction in the axonal bias after 6 weeks of denervation, but not after 4 or 12 weeks. The change in axonal bias resulted from axon sprouting across the border at 6 weeks, followed by the retraction of those axons by 12 weeks. This suggests bidirectional axonal rearrangements are associated with relatively long-durations of reorganization. Thus, diverse synaptic and morphological plasticity mechanisms could contribute to functional reorganization.