Increased Intracranial Pressure after Diffuse Traumatic Brain Injury Exacerbates Neuronal Somatic Membrane Poration but not Axonal Injury: Evidence for Primary Intracranial Pressure-Induced Neuronal Perturbation

Increased intracranial pressure (ICP) associated with traumatic brain injury (TBI) is linked to increased morbidity. Although our understanding of the pathobiology of TBI has expanded, questions remain regarding the specific neuronal somatic and axonal damaging consequences of elevated ICP, independent of its impact on cerebral perfusion pressure (CPP). To investigate this, Fischer rats were subjected to moderate TBI. Measurements of ICP revealed two distinct responses to injury. One population exhibited transient increases in ICP that returned to baseline levels acutely, while the other displayed persistent ICP elevation (>20 mm Hg). Utilizing these populations, the effect of elevated ICP on neuronal pathology associated with diffuse TBI was analyzed at 6 hours after TBI. No difference in axonal injury was observed, however, rats exhibiting persistently elevated ICP postinjury revealed a doubling of neurons with chronic membrane poration compared with rats exhibiting only transient increases in ICP. Elevated postinjury ICP was not associated with a concurrent increase in DNA damage; however, traditional histological assessments did reveal increased neuronal damage, potentially associated with redistribution of cathepsin-B from the lysosomal compartment into the cytosol. These findings indicate that persistently increased ICP, without deleterious alteration of CPP, exacerbates neuronal plasmalemmal perturbation that could precipitate persistent neuronal impairment and ultimate neuronal death.

Two Distinct Mechanisms Mediate Potentiating Effects of Depolarization on Synaptic Transmission

Two distinct mechanisms mediate potentiating effects of depolarization on synaptic transmission. Recently there has been renewed interest in a type of plasticity in which a neuron's somatic membrane potential influences synaptic transmission. We study mechanisms that mediate this type of control at a synapse between a mechanoafferent, B21, and B8, a motor neuron that receives chemical synaptic input. Previously we demonstrated that the somatic membrane potential determines spike propagation within B21. Namely, B21 must be centrally depolarized if spikes are to propagate to an output process. We now demonstrate that this will occur with central depolarizations that are only a few millivolts. Depolarizations of this magnitude are not, however, sufficient to induce synaptic transmission to B8. B21-induced postsynaptic potentials (PSPs) are only observed if B21 is centrally depolarized by ≥10 mV. Larger depolarizations have a second impact on B21. They induce graded changes in the baseline intracellular calcium concentration that are virtually essential for the induction of chemical synaptic transmission. During motor programs, subthreshold depolarizations that increase calcium concentrations are observed during one of the two antagonistic phases of rhythmic activity. Chemical synaptic transmission from B21 to B8 is, therefore, likely to occur in a phase-dependent manner. Other neurons that receive mechanoafferent input are electrically coupled to B21. Differential control of spike propagation and chemical synaptic transmission may, therefore, represent a mechanism that permits selective control of afferent transmission to different types of neurons contacted by B21. Afferent transmission to neurons receiving chemical synaptic input will be phase specific, whereas transmission to electrically coupled followers will be phase independent.