Combined Fluid Percussion Brain Injury and Entorhinal Cortical Lesion: A Model for Assessing the Interaction Between Neuroexcitation and Deafferentation

Abstract

Laboratory studies suggest that excessive neuroexcitation and deafferentation contribute to long-term morbidity following human head injury. Because no current animal model of traumatic brain injury (TBI) has been shown to combine excessive neuroexcitation and significant levels of deafferentation, we developed a rat model combining the neuroexcitation of fluid percussion TBI with subsequent entorhinal cortical (EC) deafferentation. In this paradigm, moderate fluid percussion TBI was induced in each rat, followed 24 h later by bilateral EC lesion (BEC). Six conditions were examined: (1) fluid percussion TBI followed 24 h later by bilateral EC lesion (TBEC), (2) fluid percussion TBI (TBI), (3) bilateral EC lesion (BEC), (4) sham fluid percussion TBI (SHAM), (5) TBI followed 24 h later by unilateral EC lesion (TUEC), and (6) unilateral EC lesion (UEC). The first four groups were assessed for motor (with beam-balance and beam-walk testing) and cognitive deficits (with the Morris water maze) and hippocampal morphology (with immunocytochemistry and electron microscopy). The TUEC and UEC groups were assessed for cognitive deficits alone. Motor deficits were greater in the TBEC injury than in TBI or sham alone; however, no significant difference was observed between the TBEC and BEC conditions in motor performance. Cognitive deficits were of a greater magnitude in the combined TBEC injury model relative to each individual insult. These cognitive deficits appeared to be additive for the two experimental injuries, BEC deafferentation producing deficits intermediate between TBI and TBEC insults. Morphologic analysis of the dentate gyrus molecular layer at 15 days after TBEC showed that the distribution of synaptophysin-positive presynaptic terminals was distinct from that observed after either TBI or BEC alone. Specifically, the laminar pattern of presynaptic rearrangement induced by BEC lesion did not occur after TBEC injury. The present results show that axonal injury and its attendant deafferentation, when coupled with traumatically induced neuroexcitation, produce an enhancement of the morbidity associated with TBI. Moreover, they indicate that this model can effectively be used to study the interaction between neuroexcitation and synaptic plasticity.

MT5-MMP, ADAM-10, and N-Cadherin Act in Concert To Facilitate Synapse Reorganization after Traumatic Brain Injury

“…However, under maladaptive conditions, secreted MMPs (MMP-2, -3, and -9) were persistently upregulated, suggesting the aberrant extension of lytic activity into periods when matrix stabilization is critical to synapse maturation (Falo et al, 2006;Kim et al 2005). Importantly, this persistent MMP expression and activity was correlated with attenuated synaptogenesis and long-term functional deficits (Phillips et al, 1994). These findings support MMPs as integral mediators of successful synaptic plasticity following TBI.…”

“…The duration of righting reflex suppression was used as an index of traumatic unconsciousness. Following postoperative recovery, the animals were returned to their home cages for another 24-h period, after which they were reanesthetized and subjected to bilateral entorhinal cortex lesions (Phillips et al, 1994). Lesions were performed using the UEC protocol described above.…”

“…The unilateral entorhinal cortex lesion (UEC) is a wellestablished model of hippocampal synaptic plasticity, resulting in adaptive reorganization (Steward et al, 1988). By contrast, the combination of moderate central fluid percussion TBI with bilateral entorhinal cortex lesion (TBI + BEC) leads to maladaptive synaptic plasticity, with persistent structural, functional, and behavioral deficits (Phillips and Reeves, 2001;Phillips et al, 1994). In the present study we use these models to explore how two membrane-bound matrix metalloproteinases and a synapse-associated substrate affect the success of reactive synaptogenesis induced by TBI.…”

High Blood Glucose Does Not Adversely Affect Outcome in Moderately Brain-Injured Rodents

“…Vestibulomotor and motor skills were tested using the beam balance and foot-fault tasks, respectively (Adelson et al, 1997;Chen et al, 1997;Whalen et al, 1999;Phillips et al, 1994). These tests were conducted on days 2, 3, 4, and 1440 HILL ET AL.…”

Agrin Expression during Synaptogenesis Induced by Traumatic Brain Injury

“…Central nervous system (CNS) deafferentation typically induces reactive synaptogenesis (Steward, 1989); however, when deafferentation occurs in the context of TBI, the resulting interaction of excessive neuroexcitation and traumatic axonal injury significantly reduce recovery. In order to study how this interaction affects posttraumatic synaptic plasticity, we employ a rodent injury model combining neuroexcitation and hippocampal deafferentation in the same animal, reproducing components of the persistent cognitive deficits and poor synaptic recovery of human TBI (Phillips et al, 1994). Moreover, using entorhinal cortical lesion as the deafferentation component permits direct comparison between successful, adaptive synaptogenesis, generated by unilateral entorhinal cortical lesion (UEC) alone (Steward et al, 1988), and aberrant synaptic plasticity observed when fluid-percussion TBI is combined with bilateral entorhinal cortical lesion (BEC).…”