Cortical calretinin-positive neurons: Functional and ontogenetic characteristics and their relationship to brain pathologies

•CR protein’s concentration, functional activity, and subcellular distribution may vary by cortical layer or brain region.•Studies on CR+ cortical neurons show both loss and preservation, unlike PV+ neurons, which appear selectively vulnerable.•Future research should examine variables influencing CR protein expression, including its regulatory mechanisms. Cortical GABAergic interneurons can be classified according to electrophysiological, biochemical, and/or morphological criteria. In humans, the use of calcium-binding proteins allows us to differentiate three subpopulations of GABAergic interneurons with minimal overlap. Cortical calretinin-positive neurons mainly include bipolar and double-bouquet morphologies, with a largely non-rapid and adaptive firing pattern, originating from the ganglionic eminence and the ventricular and subventricular regions of the developing brain. These cells are distributed from layer I to VI of the neocortex, with predominance in layers II and III. Given their morphology, distribution of processes, and elucidated synaptic contacts, these neurons are considered important in the control of intraminicolumnar processing through vertical inhibition. They have been extensively studied in the context of pathologies characterized by excitation/inhibition imbalance, such as Alzheimer’s disease, epilepsy, traumatic brain injury, and autism. In light of the current evidence, this review considers these aspects in depth and discusses the pathophysiological role and selective vulnerability (pathoclisis) vs. the resistance that these interneurons can present against different types of injury.