Rapid dendritic and axonal responses to neuronal insults.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system playing critical roles in basal synaptic transmission and mechanisms of learning and memory. Under normal conditions, glutamate is sequestered within synaptic vesicles (approximately 100 mM) with extracellular glutamate concentrations being limited (<1 microM), via retrieval by plasma-membrane transporters on neuronal and glial cells. In the case of central nervous system trauma, stroke, epilepsy, and in certain neurodegenerative diseases, increased concentrations of extracellular glutamate (by vesicular release, cell lysis and/or decreased glutamate transporter uptake/reversal) stimulate the overactivation of local ionotropic glutamate receptors that trigger neuronal cell death (excitotoxicity). Other natural agonists, such as domoic acid, alcohol and auto-antibodies, have also been reported to induce excitotoxicity.

Mitochondrial dysfunction and dendritic beading during neuronal toxicity.

Mitochondrial dysfunction (depolarization and structural collapse), cytosolic ATP depletion, and neuritic beading are early hallmarks of neuronal toxicity induced in a variety of pathological conditions. We show that, following global exposure to glutamate, mitochondrial changes are spatially and temporally coincident with dendritic bead formation. During oxygen-glucose deprivation, mitochondrial depolarization precedes mitochondrial collapse, which in turn is followed by dendritic beading. These events travel as a wave of activity from distal dendrites toward the neuronal cell body. Despite the spatiotemporal relationship between dysfunctional mitochondria and dendritic beads, mitochondrial depolarization and cytoplasmic ATP depletion do not trigger these events. However, mitochondrial dysfunction increases neuronal vulnerability to these morphological changes during normal physiological activity. Our findings support a mechanism whereby, during glutamate excitotoxicity, Ca(2+) influx leads to mitochondrial depolarization, whereas Na(+) influx leads to an unsustainable increase in ATP demand (Na(+),K(+)-ATPase activity). This leads to a drop in ATP levels, an accumulation of intracellular Na(+) ions, and the subsequent influx of water, leading to microtubule depolymerization, mitochondrial collapse, and dendritic beading. Following the removal of a glutamate challenge, dendritic recovery is dependent upon the integrity of the mitochondrial membrane potential, but not on a resumption of ATP synthesis or Na(+),K(+)-ATPase activity. Thus, dendritic recovery is not a passive reversal of the events that induce dendritic beading. These findings suggest that the degree of calcium influx and mitochondrial depolarization inflicted by a neurotoxic challenge, determines the ability of the neuron to recover its normal morphology.