A current project in the Welsh lab is to determine the effect of global brain hypoxia on neuronal viability, selective degeneration, and transsynaptic excitotoxicity. Our focus is on subpopulations of Purkinje cells in the cerebellar cortex which we found were selectively vulnerable to a single, transient bout of hypoxia during cardiac arrest in vivo. The mechanisms of selective vulnerability of subpopulations of Purkinje cells have become clearer in recent years, and relates to a combination of biochemical and synaptic vulnerabilities that are triggered by modulations in afferent activity in the acute post-hypoxic state. We are investigating the role that NMDA receptor upregulation plays in the recovery from hypoxia and its important role in upwardly modulating electrical synapses and thereby supporting sustained oscillatory synaptic drive. Our work has important implications for how patients in the acute post-hypoxic period are treated in order to preserve brain function, but also for other disorders in which Purkinje cells are often found to be selectively vulnerable such as in autism and traumatic brain injury.
(Figure above) A single bout of transient hypoxia induces patterned loss of Purkinje cells in cerebellar cortex.
A: In vivo paradigm showing mean arterial blood pressure over 70 min before, during, and after an hypoxic event (large arrow), which drops blood pressure to 7 mmHg for 7 min. Below are shown high-resolution traces of EKG and arterial blood pressure at various times indicated above.
B. Pattern of Purkinje cell loss from the animal treated in A revealed by calbindin immunostaining. Purkinje cell dendrites and cell bodies are lost in parasagittal zones in the posterior lobe vermis. This pattern of neuron loss is replicable in all rats and relates to their biochemical and synaptic vulnerability.