Selective dendritic susceptibility to bioenergetic, excitotoxic and redox perturbations in cortical neurons

Neurodegenerative and neurological disorders are often characterised by pathological changes to dendrites, in advance of neuronal death. Oxidative stress, energy deficits and excitotoxicity are implicated in many such disorders, suggesting a potential vulnerability of dendrites to these situations. Here we have studied dendritic vs. somatic responses of primary cortical neurons to these types of challenges in real-time. Using a genetically encoded indicator of intracellular redox potential (Grx1-roGFP2) we found that, compared to the soma, dendritic regions exhibited more dramatic fluctuations in redox potential in response to sub-lethal ROS exposure, and existed in a basally more oxidised state. We also studied the responses of dendritic and somatic regions to excitotoxic NMDA receptor activity. Both dendritic and somatic regions experienced similar increases in cytoplasmic Ca²⁺. Interestingly, while mitochondrial Ca²⁺ uptake and initial mitochondrial depolarisation were similar in both regions, secondary delayed mitochondrial depolarisation was far weaker in dendrites, potentially as a result of less NADH depletion. Despite this, ATP levels were found to fall faster in dendritic regions. Finally we studied the responses of dendritic and somatic regions to energetically demanding action potential burst activity. Burst activity triggered PDH dephosphorylation, increases in oxygen consumption and cellular NADH:NAD ratio. Compared to somatic regions, dendritic regions exhibited a smaller degree of mitochondrial Ca²⁺ uptake, lower fold-induction of NADH and larger reduction in ATP levels. Collectively, these data reveal that dendritic regions of primary neurons are vulnerable to greater energetic and redox fluctuations than the cell body, which may contribute to disease-associated dendritic damage. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.