Beam-F3 error analysis and validation of Neurally-F3 equations using realistic head models.

Due to its small size and difficulties in clearly delineating its borders in non-labelled hippocampus, the CA2 region has often been omitted from hippocampal studies. Despite limited knowledge, it has long been known that CA2 pyramidal neurons, unlike those in adjacent CA1 and CA3 regions, exhibit unusually high synaptic stability, manifested by their resistance to induction of long-term potentiation (LTP) and depression (LTD), particularly at their proximal dendrites (Chevaleyre and Siegelbaum ). For years, the molecular basis of this phenotype, similarly to the specific role of CA2 in brain function remained unclear. However, recent emerging interest in this region has revealed its molecular uniqueness (Farris et al. ) and its critical importance for social recognition memory, the ability to distinguish individuals of the same species (Hitti and Siegelbaum ; Radzicki et al. ). Additionally, several CA2-specific cellular mechanisms have recently been demonstrated to underlie the limited plasticity of this region’s neurons. These include inhibition of the H-Ras/ERK/MAP2K signaling cascade by the CA2-enriched protein, regulator of G-protein signaling 14 (RGS-14) (Lee et al. ). Another specific feature is the structure of the perineuronal net, that, unlike in CA1 or CA3, surrounds both dendrites and spines of CA2 neurons (Carstens et al. ). In addition, CA2 neurons exhibit attenuation of postsynaptic cytosolic Ca transients (Simons et al. ), a crucial mechanism in LTP/LTD formation. Given mitochondria’s role in neuronal Ca buffering (White and Reynolds ), the last mechanism may also involve the efficiency of mitochondrial Ca uptake via the Mitochondrial Calcium Uniporter (MCU) a protein recently found to be highly enriched in CA2 neurons and implicated in their distinct electrophysiological properties (Farris et al. ; Pannoni et al. , ). In addition to limited synaptic plasticity, CA2 pyramidal neurons are uniquely resistant to injury and death in various neurological disorders, particularly those involving excitotoxicity. Numerous studies report a consistent pattern of hippocampal damage: CA1 is severely affected, CA3 moderately, and CA2 minimally or not affected at all. This has been observed in post-mortem brains of patients with stroke (Bartsch et al. ), temporal lobe epilepsy (Steve et al. ) or traumatic brain injury (Maxwell et al. ) as well as in corresponding animal models (Yang et al. ; Beręsewicz-Haller et al. ). The cellular basis of CA2 resistance remains unclear. While it has been proposed that the mechanisms underlying synaptic stability, such as specific Ca dynamics, may also contribute to the protection against excitotoxicity (Leranth and Ribak ; Dudek et al. ), due to shared dependence on postsynaptic N-methyl-D-aspartate (NMDA) receptor (NMDAR) activity, this hypothesis has not been experimentally confirmed. To investigate this, we used hippocampal organotypic rat slice cultures to examine the role of MCU in CA2 resistance to excitotoxic damage.