Hippocampal formation

Summary

The hippocampal formation is a highly homologous structure across all mammals and, in primates, is located inside the temporal lobe, alongside the amygdala, medial to the inferior horn of the lateral ventricle (shown in Figure 1). The hippocampus is pivotal in recollection of facts and formation of new (including spatial) memories. In fact, long-term potentiation (modifications in synaptic strength as a result of neural activity) in certain parts of the hippocampus has been suggested as a storage mechanism for memory. Information flows into and through the hippocampus through the following principal pathways: 1- the perforant pathway from the entorhinal cortex to granule cells of the dentate gyrus; 2- the mossy fiber pathway from the granule cells of the dentate gyrus to the pyramidal cells of the CA3 region; 3- the Schaffer collateral pathway from the CA3 to the CA1 region.

The transcriptome analysis shows that 72% (n=14403) of all human protein-coding genes (n=20090) are expressed in the human hippocampal formation. Human one-to-one orthologues were investigated in pig and mouse brain, suggesting that 12373 of all mouse one-to-one orthologues (n=16320) are expressed in the mouse hippocampal formation and that 13285 of all pig orthologues (n=15829) are expressed in the pig hippocampal formation.

Figure 1. Schematic drawing of the human brain, indicating the location of hippocampal formation from a coronal perspective.

Gene classification based on regional RNA expression in human, pig and mouse hippocampal formation defines 36 genes as hippocampal formation enriched in either of the three species, and 3 out of those genes show highest expression levels in hippocampal formation in all three species.

Anatomical divisions

The hippocampal formation is an inward folded continuation of the cerebral cortex. This brain region includes the entorhinal cortex, subiculum, hippocampus proper cornu ammonis CA1-3 and dentate gyrus. The main cell types of the hippocampal formation are glutamatergic pyramidal neurons located in the cortical areas and CA regions, granule cells located in the dentate gyrus, and interneurons populating different subfields of this brain structure. Pyramidal cells in the CA regions are densely packed in a single layer. The dendrites of these cells receiving input from other regions of the hippocampal formation are located on both sides of the pyramidal cell layer in the oriens layer (superficial) and radiatum layer. The dentate gyrus granule cells are also packed in a single cell layer. These cells have their dendritic trees located in the molecular layer. The axons of these neurons are called mossy fibers and innervate the CA3 pyramidal neurons. The dentate gyrus is one of the brain regions wherein the fully developed brain still new neurons are formed (neurogenesis). These newborn neurons are formed on the interface between the polymorph layer and granular layer. More than 20 different populations of interneurons have been identified based on their location, molecular signature (calcium binding proteins, neuropeptides) and electrophysiological properties. Protein profiles of hippocampus include several interesting patterns, both in human and mouse, either related to certain cell types or selective synaptic fields, where below are a few examples.


CCK

NECAB1

CALB2


TMEM132A

GRIA1

APLP1

Regionally elevated protein expression in human

The transcriptome analysis shows that 72% (n=14403) of all human proteins (n=20090) are expressed in the hippocampal formation. 53 genes show an elevated expression level in the hippocampal formation compared to other regions of the brain.

  • 9 regionally enriched genes
  • 53 regionally elevated genes in total
  • 32 of the hippocampal formation elevated genes are elevated in other tissues than the brain.
  • 21 of the hippocampal formation elevated genes are elevated in the brain.


Table 1: Number of genes within the different categories of regionally elevated expression, in human hippocampal formation

Specificity Number of Human elevated genes
Region enriched 9
Group enriched 22
Region enhanced 22
Elevated 53

Elevated expression in hippocampal formation compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in hippocampal formation compared to all other regions), group enriched (at least four-fold higher mRNA levels in a group of 2-5 regions) and regionally enhanced (at least four-fold higher mRNA levels in hippocampal formation compared to the average of all regions), The number of genes in the individual category is shown in Table 1. In Table 2, the 9 genes with high level of regional specificity are listed.

Table 2. The 9 genes with the highest level of enriched expression in human hippocampal formation. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Regional Specificity score) corresponds to the score calculated as the fold change to the second highest region.

Gene Description Predicted location RS-score
SPATA31E1 SPATA31 subfamily E member 1 Membrane 13
ABCA4 ATP binding cassette subfamily A member 4 Membrane 6
CLDN2 Claudin 2 Membrane 6
MFRP Membrane frizzled-related protein Intracellular,Membrane 6
SCNN1A Sodium channel epithelial 1 subunit alpha Membrane 6
TRPV4 Transient receptor potential cation channel subfamily V member 4 Membrane 6
C1QTNF9 C1q and TNF related 9 Secreted 4
C1QTNF9B C1q and TNF related 9B Secreted 4
FBP2 Fructose-bisphosphatase 2 Intracellular 4

Hippocampus share many regionally elevated genes with other forebrain regions, such as cerebral cortex, amygdala and basal ganglia. Both neuronal and glial proteins are found among the regionally elevated targets.


ICAM5

MT1A

NRGN

Regionally elevated protein expression in mouse

Although the volume of the hippocampus is much smaller in mice than in humans, the basic hippocampal architecture is common to both species. However, substantial species differences exist, which argue against the frequent portrayal of hippocampus as a phylogenetically primitive brain region.

The transcriptome analysis shows that 62% (n=12373) of all mouse one-to-one orthologues genes (n=16320) are expressed in the hippocampal formation. 91 genes show an elevated expression in hippocampal formation compared to other regions of the brain.

Table 3: Number of genes within the different categories of regionally elevated expression, in mouse hippocampal formation

Specificity Number of Mouse elevated genes
Region enriched 19
Group enriched 56
Region enhanced 16
Elevated 91

Figure 2. Schematic drawing of the mouse brain, indicating the location of hippocampal formation from a coronal perspective.

Table 4: The 12 genes with the highest level of enriched expression in mouse hippocampal formation. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Region Specificity score) corresponds to the score calculated as the fold change to the second highest region.

Gene Description Predicted location RS-score
DSP Desmoplakin Intracellular 23
LCT Lactase Membrane 15
RTL3 Retrotransposon Gag like 3 Intracellular 9
SPINK8 Serine peptidase inhibitor Kazal type 8 (putative) Secreted 9
PRSS8 Serine protease 8 Membrane,Secreted 8
CRLF1 Cytokine receptor like factor 1 Intracellular,Secreted 7
PRPH2 Peripherin 2 Membrane 7
GNAT1 G protein subunit alpha transducin 1 Intracellular 6
FERMT1 Fermitin family member 1 Intracellular 5
KLK8 Kallikrein related peptidase 8 Intracellular,Secreted 5
PDC Phosducin Intracellular 5
CTXND1 Cortexin domain containing 1 Membrane 4


ITPKA

PCP4

ARFGEF1

Regionally elevated protein expression in pig

The volume of the pig hippocampus lies between that of mice and humans; however, the basic hippocampal architecture is common to all 3 species.

The transcriptome analysis shows that 66% (n=13285) of all pig genes (n=15829) are expressed in the hippocampal formation. 106 genes show an elevated expression in hippocampal formation compared to other regions of the brain.

Table 5: Number of genes within the different categories of regionally elevated expression, in pig hippocampal formation

Specificity Number of Pig elevated genes
Region enriched 8
Group enriched 80
Region enhanced 18
Elevated 106

Figure 3. Schematic drawing of the pig brain, indicating the location of hippocampal formation from a coronal perspective.

Elevated expression in hippocampal formation compared to other brain regions is divided into three different categories; regionally enriched (at least four-fold higher mRNA levels in hippocampal formation compared to all other regions), group enriched (at least four-fold higher mRNA levels in a group of 2-5 regions) and regionally enhanced (at least four-fold higher mRNA levels in hippocampal formation compared to the average of all regions), The number of genes in the individual category is shown in Table 5. In Table 6, the 8 enriched genes are listed.

Table 6: The 8 genes with the highest level of enriched expression in pig hippocampal formation. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. RS-score (Regional Specificity score) corresponds to the score calculated as the fold change to the second highest region.

Gene Description Predicted location RS-score
AMHR2 Anti-Mullerian hormone receptor type 2 Intracellular,Membrane 11
TRIM10 Tripartite motif containing 10 Intracellular 11
NEUROG2 Neurogenin 2 Intracellular 10
NPY2R Neuropeptide Y receptor Y2 Membrane 6
FIBCD1 Fibrinogen C domain containing 1 Intracellular 5
KCNG2 Potassium voltage-gated channel modifier subfamily G member 2 Membrane 5
KRT27 Keratin 27 Intracellular 5
MYLK3 Myosin light chain kinase 3 Membrane 5

Extended information

Extended human hippocampal formation tissue section

The standard setup in the Tissue Atlas, that profiles the human tissues, is based on Tissue Micro array technique, saving valuable tissue material as well as reagents but still provides a good tissue representation for protein profiling. However, due to the complex nature of the hippocampus, with different cell types and subfields, a larger sample to better understand the protein location is used for selected targets. Below, the selected 27 proteins profiled on extended hippocampus tissue material are listed.

Table 7. These 27 genes have been analyzed using extended hippocampal formation samples.

Gene Gene description Staining pattern
BHLHE22 Basic helix-loop-helix family member e22 Nuclear staining in a subset of neurons.
CHRNA5 Cholinergic receptor nicotinic alpha 5 subunit Strong staining in astrocytes.
CREG2 Cellular repressor of E1A stimulated genes 2 Cytoplasmic positivity in synapses and neuronal projections.
DCC DCC netrin 1 receptor Strong projection positivity.
DCX Doublecortin Cytoplasmic positivity in neurons.
DNER Delta/notch like EGF repeat containing Positive in a few neurons.
FGF2 Fibroblast growth factor 2 Nuclear staining in glia.
GRIA3 Glutamate ionotropic receptor AMPA type subunit 3 Weak to moderate staining in neuropil.
GRIK4 Glutamate ionotropic receptor kainate type subunit 4 Strong projection and synapse staining.
GRIN1 Glutamate ionotropic receptor NMDA type subunit 1 Synaptic and cytoplasmic staining in neurons.
KCNG2 Potassium voltage-gated channel modifier subfamily G member 2 Distinct astrocyte end-feet staining in hippocampus.
MAP2 Microtubule associated protein 2 Strong cytoplasmic positivity in neuronal cells.
NEFL Neurofilament light Intense neuronal projection positivity.
NPTX1 Neuronal pentraxin 1 Strong cytoplasmic staining in neurons. Strong synaptic and neuronal projection staining.
NTRK2 Neurotrophic receptor tyrosine kinase 2 Strong cytoplasmic positivity in glial cells.
PDE1B Phosphodiesterase 1B Strong neuronal staining and moderate synaptic staining.
PRKCE Protein kinase C epsilon Synaptic positivity.
PRKCG Protein kinase C gamma Cytoplasmic positivity in neuronal cells.
PTPRN Protein tyrosine phosphatase receptor type N Cytoplasmic staining in neuronal cells. Synaptic positivity.
PTPRZ1 Protein tyrosine phosphatase receptor type Z1 Strong in neurons.
RTP5 Receptor transporter protein 5 (putative) Cytoplasmic staining in neuronal cells.
RUNDC3A RUN domain containing 3A Strong extracellular staining in hippocampus.
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