Hypoxia is a condition characterized by inadequate oxygen levels in tissues or organs, which can have widespread and detrimental effects on various physiological processes. Sufficient oxygen supply is fundamental for maintaining normal brain functions and synaptic transmission. Prolonged hypoxia as in an ischemic stroke can lead to irreversible brain injury with symptoms like epilepsy, speech and language deficits or even paralysis. In acute hypoxia, the cells adapt in different ways to the decreased oxygen supply for protection of neurons, including decreased synaptic signaling or changes in excitation and inhibition of neuronal and glial cells.

Key factors of the cellular response to low oxygen are a group of heterodimeric transcription factors, the hypoxia-inducible factors (HIF-1, HIF-2 and HIF-3). HIFs alter the expression of oxygen-related genes and play an important role during brain development and neural regeneration after hypoxic events. The function of HIFs thereby varies based on the specific brain region or cell type, such as neurons or astrocytes. In addition, the isoforms HIF-1 and HIF-2 exhibit different, sometimes opposing effects on cellular adaptation to hypoxia.

Synapses are highly susceptible to changes in oxygen availability based on their high energetic demand. Although many of the response mechanisms to hypoxia take part at the synapse, the exact role of HIF-2 in synaptic transmission and plasticity is not yet known.

Previous studies found implications of HIF-2 on brain development, learning and memory in vivo under normoxic conditions and under hypoxia in vitro. Therefore, this study investigates the functions of HIF-2 in synaptogenesis and synaptic transmission in a mouse model of a brain-specific HIF-2α knockout (KO) on a molecular level. Under normoxic conditions, HIF-2α had no major impact on hippocampal development and synaptic ultrastructure in vivo. Additionally, a global HIF-2α KO did not lead to any significant differences in the expression of synapse-associated genes in cortex and hippocampus of adult animals, even under environmentally enriched conditions. However, in an in vitro model of brain hypoxia, using a neuron-astrocyte co-culture system, HIF-2α abundance in astrocytes played a significant role. In the absence of astrocytic HIF-2α, the neuronal adaptation to hypoxic stress is dampened, independent of the neuronal genotype. Neurons exhibited reduced activation of hypoxia-responsive genes like Vegf and Phd2, along with increased expression of genes linked to the excitatory glutamatergic system and decreased expression of genes related to the inhibitory GABAergic system.

Astrocytes recently emerged as new regulators in synaptic activation by interacting with neurons through paracrine effects. In this study, astrocyte-derived neurotrophic factors like Vegf and Epo were less expressed when HIF-2α was knocked out in astrocytes, potentially resulting in the disturbed fine-tuning of neuronal response to hypoxia and altered balance between excitatory and inhibitory synapses.

Collectively, astrocytic HIF-2α emerged as a key player for the interplay between astrocytes and neurons during neuronal adaptation mechanisms to hypoxia whereas neuronal HIF-2α seems to be of only limited importance at the synapse. Since synapses are crucial for communication between neurons and play a vital role in cognitive functions, understanding how they respond to hypoxia can shed light on the mechanisms underlying cognitive impairment, memory deficits and various neurological disorders that are associated with oxygen deprivation in the brain.