Mitochondrial Dysfunction and Dendritic Beading during Neuronal Toxicity

Abstract

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.Mitochondrial dysfunction, dendritic spine remodeling, and the formation of neuritic beads are early hallmarks of neuronal toxicity induced in a variety of pathological conditions (1-6). In particular, in Alzheimer disease, the existence of extracellular amyloid plaques and intracellular neurofibrillary tangles have been associated with neuritic beading, spine loss, neurite breakage, and shaft atrophy (7-10).An understanding of the importance of mitochondrial dysfunction in neurological diseases continues to grow. Mitochondria are highly dynamic organelles with their trafficking and elongated morphology being regulated by neuronal (11, 12) and mitochondrial (13) activity. It appears that mitochondrial transport, morphology, and function are affected by physiological processes such as synaptic transmission and pathological processes such as excitotoxicity.Despite the fact that mitochondrial dysfunction and dendritic beading are both initiated by glutamate excitotoxicity, these events are believed to be independent due to their distinct requirements for Ca 2ϩ (1-4, 6, 14) versus Na ϩ (2, 3) influx. Moreover, dendritic beading occurs much more rapidly than Ca 2ϩ -dependent excitotoxic cell death (2, 3). ...

Excessive Na+/H+ Exchange in Disruption of Dendritic Na+ and Ca2+ Homeostasis and Mitochondrial Dysfunction following in Vitro Ischemia

“…The vulnerability of neuronal dendrites is characterized by the initial membrane depolarization, mitochondrial structure collapse, and dendritic beading in the dendrites and the subsequent propagation toward the soma during hypoxia and activation of NMDA receptors (1,6). Our current study illustrates that blocking of NHE-1 activity attenuated many similar changes in the dendrites following OGD/REOX.…”

“…Our current study illustrates that blocking of NHE-1 activity attenuated many similar changes in the dendrites following OGD/REOX. Therefore, concerted activation of NHE-1 and NCX rev may also play a role (6,42). Sustained loss of ⌿ m will eventually trigger the opening of the permeability transition pore and release of Ca 2ϩ m and collapse of mitochondria bioenergetics (6).…”

“…Therefore, concerted activation of NHE-1 and NCX rev may also play a role (6,42). Sustained loss of ⌿ m will eventually trigger the opening of the permeability transition pore and release of Ca 2ϩ m and collapse of mitochondria bioenergetics (6). In the current study, most of the Ca 2ϩ m accumulation occurred before ⌿ m decreased below 50% and remained at a sustained level when ⌿ m was ϳ45% of control in the soma and ϳ20% of control in the Sm-dendrites.…”

“…On the other hand, excessive Ca 2ϩ entry plays a role in the long lasting structural damage and delayed recovery in hippocampal slices in response to NMDA (4,5). A correlation between dendritic bead formation and ATP reduction/mitochondrial dysfunction has been demonstrated in cultured hippocampal neurons following glutamate exposure (6). However, the relationship between selective dendritic damage, loss of Na ϩ and Ca 2ϩ homeostasis, and mitochondrial dysfunction following ischemia remains to be defined.…”

Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways

“…Primary hippocampal cultures were prepared as described previously (Greenwood et al, 2007). Briefly, 1-to 2-day-old Sprague Dawley rats were killed by cervical dislocation and decapitated.…”