Prior investigations of traumatic axonal injury (TAI), and pharmacological treatments of TAI pathology, have focused exclusively on the role of myelinated axons, with no systematic observations directed towards unmyelinated axon pathophysiology. Recent electrophysiological evidence, however, indicates that unmyelinated axons are more vulnerable than myelinated axons in a rodent model of experimental TAI. Given their susceptibility to TAI, the present study examines whether unmyelinated axons also respond differentially to FK506, an immunophilin ligand with well-established neuroprotective efficacy in the myelinated fiber population. Adult rats received 3.0 mg/kg FK506 intravenously at 30 min prior to midline fluid percussion injury. In brain slice electrophysiological recordings, conducted at 24 h postinjury, compound action potentials (CAPs) were evoked in the corpus callosum, and injury effects quantified separately for CAP waveform components generated by myelinated axons (N1 wave) and unmyelinated axons (N2 wave). The amplitudes of both CAP components were suppressed postinjury, although this deficit was 16% greater for the N2 CAP. While FK506 treatment provided significant neuroprotection for both N1 and N2 CAPs, the drug benefit for the N2 CAP amplitude was 122% greater than that for the N1 CAPs, and improved postinjury strength-duration and refractoriness properties only in N2 CAPs. Immunocytochemical observations, of TAI reflected in intra-axonal pooling of amyloid precursor protein, indicated that FK506 reduced the extent of postinjury impairments to axonal transport and subsequent axonal damage. Collectively, these studies further substantiate a distinctive role of unmyelinated axons in TAI, and suggest a highly efficacious neuroprotective strategy to target this axonal population.

Although rodent models of traumatic brain injury (TBI) reliably produce cognitive and motor disturbances, behavioral characterization resulting from left and right hemisphere injuries remains unexplored. Here we examined the functional consequences of targeting the left versus right parietal cortex in lateral fluid percussion injury, on Morris water maze (MWM) spatial memory tasks (fixed platform and reversal) and neurological motor deficits (neurological severity score and rotarod). In the MWM fixed platform task, right lateral injury produced a small delay in acquisition rate compared to left. However, injury to either hemisphere resulted in probe trial deficits. In the MWM reversal task, left-right performance deficits were not evident, though left lateral injury produced mild acquisition and probe trial deficits compared to sham controls. Additionally, left and right injury produced similar neurological motor task deficits, impaired righting times, and lesion volumes. Injury to either hemisphere also produced robust ipsilateral, and modest contralateral, morphological changes in reactive microglia and astrocytes. In conclusion, left and right lateral TBI impaired MWM performance, with mild fixed platform acquisition rate differences, despite similar motor deficits, histological damage, and glial cell reactivity. Thus, while both left and right lateral TBI produce cognitive deficits, laterality in mouse MWM learning and memory merits consideration in the investigation of TBI-induced cognitive consequences.

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Neuroglia play an important role in synaptogenesis after traumatic brain injury (TBI). The magnitude of glial response appears to be injury specific, potentially facilitating or attenuating synaptic recovery. Our prior studies also show that matrix metalloproteinases (MMPs) are differentially upregulated within reactive glia as a function of injury. Here, we contrasted glial response in models of adaptive (unilateral entorhinal cortex lesion; UEC) or maladaptive (combined fluid percussion injury and bilateral entorhinal cortex lesion; TBI+BEC) synaptic plasticity. Rats received UEC or TBI+BEC and were sacrificed 7d postinjury. Excised brains were processed for immunohistochemistry (IHC) with antibodies specific to astrocytes (GFAP), microglia (Iba‐1) and membrane‐bound MMPs, ADAM‐10 and MT5‐MMP. Confocal images revealed an increase in GFAP and Iba‐1 over deafferented neuropil in both models compared to uninjured controls. Microglial response was similar in the two models, however, TBI+BEC showed a greater GFAP increase across both dentate molecular and granule cell layers. Only GFAP+ cells were co‐labeled ADAM‐10 and MT5‐MMP. Results suggest that extent and distribution of TBI glial response is injury specific. Moreover, astrocytic ADAM‐10 and MT5‐MMP expression during reactive plasticity is a potential therapeutic target to facilitate synaptogenesis after TBI. Supported by: NIH grants NS44372, NS57758.