Selective vulnerability of hippocampal CA1 and CA3 pyramidal cells: What are possible pathomechanisms and should more attention be paid to the CA3 region in future studies?

Transient ischemia and reperfusion selectively damage neurons in brain, with hippocampal pyramidal cells being particularly vulnerable. Even within hippocampus, heterogeneous susceptibility is evident, with higher vulnerability of CA1 versus CA3 neurons described for several decades. Therefore, numerous studies have focused exclusively on CA1. Pediatric cardiac surgery is increasingly focusing on studies of hippocampal structures, and a negative impact of cardiopulmonary bypass on the hippocampus cannot be denied. Recent studies show a shift in selective vulnerability from neurons of CA1 to CA3. This review shows that cell damage is increased in CA3, sometimes stronger than in CA1, depending on several factors (method, species, age, observation period). Despite a highly variable pattern, several markers illustrate greater damage to CA3 neurons than previously assumed. Nevertheless, the underlying cellular mechanisms have not been fully deciphered to date. The complexity is reflected in possible pathomechanisms discussed here, with numerous factors (NMDA, kainate and AMPA receptors, intrinsic oxidative stress potential and various radicals, AKT isoforms, differences in vascular architecture, ratio of pro- and anti-apoptotic Bcl-2 factors, vulnerability of interneurons, mitochondrial dysregulation) contributing to either enhanced CA1 or CA3 vulnerability. Furthermore, differences in expressed genome, proteome, metabolome, and transcriptome in CA1 and CA3 appear to influence differential behavior after damaging stimuli, thus metabolomics-, transcriptomics-, and proteomics-based analyses represent a viable option to identify pathways of selective vulnerability in hippocampal neurons. These results emphasize that future studies should focus on the CA3 field in addition to CA1, especially with regard to improving therapeutic strategies after ischemic/hypoxic brain injury.