Interneurons that Co-Express Parvalbumin and Calbindin

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Human Uniqueness Compared to "Great Apes": 
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Humans evolved co-expression of calbindin and parvalbumin in cortical interneurons. The calcium-binding proteins calbindin D28K (CB) and parvalbumin (PV) are expressed by many interneurons in the cerebral cortex of mammals that have been studied. In the most commonly studied taxa, rodents and nonhuman primates, CB and PV are expressed by different, non-overlapping classes interneurons. In humans, however, it has been reported that human temporal cortex contains a population of interneurons that co-express CB and PV (del Rio and DeFelipe, 1997). This could represent a human specialization, but given the lack of information about other, nonhuman ape species, it is not possible to exclude the possibility that this is a hominid or hominoid specialization.



Timing of appearance of the difference in the Hominin Lineage as a defined date or a lineage separation event. The point in time associated with lineage separation events may change in the future as the scientific community agrees upon better time estimates. Lineage separation events are defined in 2017 as:

  • the Last Common Ancestor (LCA) of humans and old world monkeys was 25,000 - 30,000 thousand (25 - 30 million) years ago
  • the Last Common Ancestor (LCA) of humans and chimpanzees was 6,000 - 8,000 thousand (6 - 8 million) years ago
  • the emergence of the genus Homo was 2,000 thousand (2 million) years ago
  • the Last Common Ancestor (LCA) of humans and neanderthals was 500 thousand years ago
  • the common ancestor of modern humans was 100 - 300 thousand years ago

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Background Information: 

In the mammalian brain, inhibitory interneurons that release GABA (gamma-aminobutyric acid) play a critical role in modulating network activity. These interneurons send local projections and depress the activity of neighboring principal neurons. Many interneurons can be classified based on what calcium-binding protein they express. Calcium is an important second messenger in many cellular pathways, so neurons that have different calcium buffering capacities will have different physiological properites. Interneurons in the cortex can express parvalbumin (PV), calbindin (CB), or calretinin (CR). The majority of the research on interneuron populations has been done in rodents, demonstrating that these populations can be overlapping (Makram et al., 2004). Primate research shows that this overlap is far less (Sherwood et al., 2007).

The Human Difference: 

In fact, the greatest degree of calcium-binding protein colocalization in primates has been found in human temporal cortex, where 14% of PV-expressing interneurons also express CB (de Rio & DeFelipe, 1997). In most other areas, this overlap is quite minimal. The temporal cortex is involved in memory formation and consolidation among other things. So this greater degree of overlap in humans may have some functional relevance, contributing to human uniqueness. Other studies looking at macaques found that, in the basolateral amygdala, approximately 25% of PV-expressing interneurons also express CB (Mascagni et al., 2009). This brain area is involved in fear memory and emotional arousal. Studies looking at the developing visual cortex in macaques have found that most PV-expressing interneurons also co-express CB before birth yet lose this co-expression with development (Yan, Van Brederode, & Hendrickson, 1995). Further studies directly comparing humans and nonhuman primates are needed. Of course, histology experiments with humans are more difficult as post-mortem brains are required. Additionally, it is important to note that interneurons that express PV and CB are just a subpopulation of all the interneurons in the brain. Additionally, there are other genetic markers for interneurons that are not calcium-binding proteins, such as somatostatin and cholecystokinin, that may also be co-expressed with calcium-binding proteins and undoubtedly has some functional significance.

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  1. Immunohistochemical characterization of parvalbumin-containing interneurons in the monkey basolateral amygdala., Mascagni, F, Muly E C., Rainnie D G., and McDonald A J. , Neuroscience, 2009 Feb 18, Volume 158, Issue 4, p.1541-50, (2009)
  2. The evolution of neuron types and cortical histology in apes and humans, Sherwood, CC, and Hof PR , Evolution, Volume 4, p.a0005, (2007)
  3. Interneurons of the neocortical inhibitory system., Markram, Henry, Toledo-Rodriguez Maria, Wang Yun, Gupta Anirudh, Silberberg Gilad, and Wu Caizhi , Nat Rev Neurosci, 2004 Oct, Volume 5, Issue 10, p.793-807, (2004)
  4. Colocalization of parvalbumin and calbindin D-28k in neurons including chandelier cells of the human temporal neocortex., del Río, M R., and DeFelipe J , J Chem Neuroanat, 1997 Mar, Volume 12, Issue 3, p.165-73, (1997)
  5. Transient co-localization of calretinin, parvalbumin, and calbindin-D28K in developing visual cortex of monkey., Yan, Y H., Van Brederode J F., and Hendrickson A E. , J Neurocytol, 1995 Nov, Volume 24, Issue 11, p.825-37, (1995)