Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1263 2023-07-24 09:30:25 |
2 format correct Meta information modification 1263 2023-07-27 05:01:11 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Zhao, F.; Behnisch, T. Hippocampal Formation and Unique Properties of CA2 Region. Encyclopedia. Available online: https://encyclopedia.pub/entry/47171 (accessed on 17 April 2024).
Zhao F, Behnisch T. Hippocampal Formation and Unique Properties of CA2 Region. Encyclopedia. Available at: https://encyclopedia.pub/entry/47171. Accessed April 17, 2024.
Zhao, Fang, Thomas Behnisch. "Hippocampal Formation and Unique Properties of CA2 Region" Encyclopedia, https://encyclopedia.pub/entry/47171 (accessed April 17, 2024).
Zhao, F., & Behnisch, T. (2023, July 24). Hippocampal Formation and Unique Properties of CA2 Region. In Encyclopedia. https://encyclopedia.pub/entry/47171
Zhao, Fang and Thomas Behnisch. "Hippocampal Formation and Unique Properties of CA2 Region." Encyclopedia. Web. 24 July, 2023.
Hippocampal Formation and Unique Properties of CA2 Region
Edit

Parkinson’s disease (PD) is a neurodegenerative disease that affects both motor and non-motor functions. Although motor impairment is a prominent clinical sign of PD, additional neurological symptoms may also occur, particularly in the preclinical and prodromal stages. Among these symptoms, social cognitive impairment is common and detrimental. Interestingly, the hippocampal CA2 region, with its unique properties, has attracted the attention of scientists due to its potential association with social cognitive functions.

memory hippocampus CA2

1. Introduction

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra, a loss that is unfortunately irreversible [1]. Studies have described many non-motor symptoms that appear in the early stages of PD [2][3], in particular, social cognitive decline such as perception, language, and decision-making [4], as well as temporal-order memory deficits [5]. Interestingly, the hippocampal CA2 region, with its unique properties, has attracted the attention of scientists due to its potential association with social cognitive functions.

2. The Hippocampal Formation and the Unique Properties of the CA2 Region

The hippocampal formation (HF) is located within the medial temporal lobe in all mammalian species, close to the adjacent cerebral cortex, enabling its many crucial connections to various cortical regions. HF is a critical functional unit that contributes significantly to many vital cognitive processes in both humans and animals, including learning and memory [6], fear processing [7], spatial orientation [8], and social behavior [9]. HF includes the cornu ammonis (CA) and the dentate gyrus areas. Ramón and Cajal divided the CA into two parts: the superior region, composed predominantly of small-body neurons, and the inferior region, composed of larger vertebral-body neurons. This division was later refined by Rafael Lorente de Nó, who identified four subregions within the CA area: CA1, CA2, CA3, and CA4. He observed that the neurons in CA2 and CA3 were larger than those in CA1 and that the CA2 subregion did not receive mossy fiber projections from the DG but instead received inputs via the Schaffer collateral fibers originating in CA3 [10]. However, Dudek et al. determined that the extent to which mossy fibers project into CA2 and synapse onto CA2 pyramidal neurons is species dependent [11]. The nomenclature and function have long been subjects of controversy, with debate over whether it is a distinct or transitional region between CA1 and CA3. However, current research suggests that CA2 possesses a unique biological structure [12], which requires further investigation in humans [13]. Interestingly, researchers have also indicated that CA2 may be proportionally larger in primates than in rodents [11].
CA2 exhibits unique morphological features, including a more loosely packed stratum pyramidal in comparison to CA1. In addition, pyramidal neurons in CA2 have an oval and dense soma, which is the largest among excitatory neurons within CA regions. Neurons in CA2 are also characterized by a hyperpolarized resting membrane potential and display specific action potential firing patterns [14]. Furthermore, the afferent and efferent connections of the CA2 field have distinct origins and terminations compared to other regions of the hippocampal formation. For instance, an optogenetic study demonstrated functional monosynaptic inputs from the DG via longitudinal projections to the CA2 area [15]. Other data suggest that CA2 neurons have more extensive functional synaptic connections with the deep area of CA1 than with the superficial layer [15] and that they also exhibit stronger innervation to CA1 than to CA3 [14]. However, the degree of synaptic connectivity between layer III EC afferents and distant branches of CA2 neurons may vary between species. In particular, fibers originating from layer III EC neurons and traversing the stratum lacunosum-moleculare in the CA1 region play a role in this variation [14].
Recently, CA2 has been shown to play a central role in social behavior. Molecular markers such as Purkinje cell protein 4 (PCP4), a regulator of G protein signaling 14 protein (RGS14), and striatum-enriched protein–tyrosine phosphatase (STEP), help to identify the specific population of neurons in the CA2 region [11][12][15][16][17][18]. Lee et al. demonstrated that RGS14 deletion imparts a substantial capacity for SC-CA2 synapse, whereas wild-type CA2 neurons exhibited little LTP [16]. Researchers discovered a loss of inhibitory neurons in CA2 in a neuropsychiatric disorder-like mouse model. These mice exhibited impaired social cognition and reduced synaptic plasticity in CA2, which may be related to the loss of PV+ interneurons [19]. In addition, CA2 activates a disinhibitory circuit from the lateral septum to the ventromedial hypothalamus (LS-VMHv1), which is modulated by the signaling pathway of arginine vasopressin (AVP), a hormone and neurotransmitter, to promote social aggression [20]. Dysfunctions in this signaling pathway have also been associated with neuropsychiatric disorders such as depression, anxiety, and autism spectrum disorders. Furthermore, researchers have speculated that the CA2 region is crucial for the formation and retrieval of memories related to social encounters [21]. Although arginine vasopressin receptor 1B (AVPR1B) mRNA is highly expressed in CA2 pyramidal neurons in both humans and rodents [12][21], one study demonstrated that AVPR1B -deficient mice were unable to recognize other mice in the “social novelty test” and also showed impaired chronological-order memory [22].
Another test showed that AVPR1B knockout mice could not discriminate the object they explored and recognize its location like the control group [23]. AVPR1B deficiency in CA2 impaired social memory enhancement [24]. In addition to AVPR1B, oxytocin receptors, another social neuropeptide receptor, are also highly expressed in CA2 [25][26]. In addition, genetic evidence suggests that CA2 injury impairs social recognition in mice [22]. Interestingly, the CA2 area of the hippocampus is the only region that receives vasopressinergic input from both the paraventricular nuclei of the hypothalamus and the supramammillary nuclei (SuM)—a critical factor in the regulation of social cognitive behaviors [27][28][29][30]. Interestingly, terminals belonging to the SuM have been found to express substance P [11], which plays a central role in PD. Furthermore, research suggests that these particular SuM afferents expressing substance P specifically target CA2 in rats and have the ability to influence plasticity in pyramidal neurons located in CA2 [31]. The SuM-to-CA2 projection has also been reported in monkeys and humans and occurs during early embryonic development [32]. The reason for enhanced social performance may involve the circuit from dorsal CA2 to ventral CA1 [33], spike timing-dependent plasticity in CA2 [34], the negative regulatory role of CA2 in hippocampal sharp-wave ripples [35][36], and the distinct dendritic properties of CA2 compared to CA1 [37]. In addition, mineralocorticoid receptors (MRs) have been shown to facilitate CA2-dependent behaviors [38].
In summary, CA2 pyramidal neurons possess numerous distinctive morphological, physiological, and synaptic characteristics, as well as intrinsic and extrinsic connections that distinguish them from other CA regions (see Table 1), and more DEGs that are unique for CA2 regions have been described [11]. Despite the identification of several molecular markers in this area by current studies, our understanding of its functional properties, including its unique physiology, signaling and resilience, and behavioral role, particularly in synaptic plasticity and PD, remains limited.
Table 1. Proteins that are highly expressed in CA2 neurons and their functions.

References

  1. Hague, S.M.; Klaffke, S.; Bandmann, O. Neurodegenerative disorders: Parkinson’s disease and Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 2005, 76, 1058–1063.
  2. Chaudhuri, K.R.; Healy, D.G.; Schapira, A.H.V. Non-motor symptoms of Parkinson’s disease: Diagnosis and management. Lancet Neurol. 2006, 5, 235–245.
  3. Aarsland, D. Cognitive impairment in Parkinson’s disease and dementia with Lewy bodies. Parkinsonism Relat. Disord. 2016, 22 (Suppl. S1), S144–S148.
  4. Palmeri, R.; Buono, V.L.; Corallo, F.; Foti, M.; Di Lorenzo, G.; Bramanti, P.; Marino, S. Nonmotor Symptoms in Parkinson Disease: A Descriptive Review on Social Cognition Ability. J. Geriatr. Psychiatry Neurol. 2017, 30, 109–121.
  5. Brown, S.W.; Smith-Petersen, G.A. Time perception and temporal order memory. Acta Psychol. 2014, 148, 173–180.
  6. van Strien, N.M.; Cappaert, N.L.M.; Witter, M.P. The anatomy of memory: An interactive overview of the parahippocampal–hippocampal network. Nat. Rev. Neurosci. 2009, 10, 272–282.
  7. Goosens, K.A. Hippocampal regulation of aversive memories. Curr. Opin. Neurobiol. 2011, 21, 460–466.
  8. Buzsáki, G.; Moser, E.I. Memory, navigation and theta rhythm in the hippocampal-entorhinal system. Nat. Neurosci. 2013, 16, 130–138.
  9. Felix-Ortiz, A.C.; Tye, K.M. Amygdala Inputs to the Ventral Hippocampus Bidirectionally Modulate Social Behavior. J. Neurosci. 2014, 34, 586–595.
  10. Fairént, A.; Regidort, J.; Kruger, L. The Cerebral Cortex of the Mouse (A First Contribution—The “Acoustic” Cortex). Somatosens. Mot. Res. 1992, 9, 3–36.
  11. Dudek, S.M.; Alexander, G.M.; Farris, S. Rediscovering area CA2: Unique properties and functions. Nat. Rev. Neurosci. 2016, 17, 89–102.
  12. Lein, E.S.; Callaway, E.M.; Albright, T.D.; Gage, F.H. Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. J. Comp. Neurol. 2005, 485, 20426.
  13. Insausti, R.; Muñoz-López, M.; Insausti, A.M. The CA2 hippocampal subfield in humans: A review. Hippocampus 2023, 33, 712–729.
  14. Chevaleyre, V.; Siegelbaum, S.A. Strong CA2 Pyramidal Neuron Synapses Define a Powerful Disynaptic Cortico-Hippocampal Loop. Neuron 2010, 66, 560–572.
  15. Kohara, K.; Pignatelli, M.; Rivest, A.J.; Jung, H.-Y.; Kitamura, T.; Suh, J.; Frank, D.; Kajikawa, K.; Mise, N.; Obata, Y.; et al. Cell type–specific genetic and optogenetic tools reveal hippocampal CA2 circuits. Nat. Neurosci. 2013, 17, 269–279.
  16. Lee, S.E.; Simons, S.B.; Heldt, S.A.; Zhao, M.; Schroeder, J.P.; Vellano, C.P.; Cowan, D.P.; Ramineni, S.; Yates, C.K.; Feng, Y.; et al. RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proc. Natl. Acad. Sci. USA 2010, 107, 16994–16998.
  17. Shinohara, Y.; Hosoya, A.; Yahagi, K.; Ferecskó, A.S.; Yaguchi, K.; Sík, A.; Itakura, M.; Takahashi, M.; Hirase, H. Hippocampal CA3 and CA2 have distinct bilateral innervation patterns to CA1 in rodents. Eur J Neurosci. 2012, 35, 702–710.
  18. Evans, P.R.; Parra-Bueno, P.; Smirnov, M.S.; Lustberg, D.J.; Dudek, S.M.; Hepler, J.R.; Yasuda, R. RGS14 Restricts Plasticity in Hippocampal CA2 by Limiting Postsynaptic Calcium Signaling. eNeuro 2018, 5, ENEURO.0353-17.
  19. Piskorowski, R.A.; Nasrallah, K.; Diamantopoulou, A.; Mukai, J.; Hassan, S.I.; Siegelbaum, S.A.; Gogos, J.A.; Chevaleyre, V. Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome. Neuron 2016, 89, 163–176.
  20. Leroy, F.; Park, J.; Asok, A.; Brann, D.H.; Meira, T.; Boyle, L.M.; Buss, E.W.; Kandel, E.R.; Siegelbaum, S.A. A circuit from hippocampal CA2 to lateral septum disinhibits social aggression. Nature 2018, 564, 213–218.
  21. Young, W.; Li, J.; Wersinger, S.; Palkovits, M. The vasopressin 1b receptor is prominent in the hippocampal area CA2 where it is unaffected by restraint stress or adrenalectomy. Neuroscience 2006, 143, 1031–1039.
  22. Hitti, F.L.; Siegelbaum, S.A. The hippocampal CA2 region is essential for social memory. Nature 2014, 508, 88–92.
  23. DeVito, L.M.; Konigsberg, R.; Lykken, C.; Sauvage, M.; Young, W.S.; Eichenbaum, H. Vasopressin 1b Receptor Knock-Out Impairs Memory for Temporal Order. J. Neurosci. 2009, 29, 2676–2683.
  24. Smith, A.S.; Avram, S.K.W.; Cymerblit-Sabba, A.; Song, J.; Young, W.S. Targeted activation of the hippocampal CA2 area strongly enhances social memory. Mol. Psychiatry 2016, 21, 1137–1144.
  25. Lin, Y.-T.; Hsieh, T.-Y.; Tsai, T.-C.; Chen, C.-C.; Huang, C.-C.; Hsu, K.-S. Conditional Deletion of Hippocampal CA2/CA3a Oxytocin Receptors Impairs the Persistence of Long-Term Social Recognition Memory in Mice. J. Neurosci. 2017, 38, 1218–1231.
  26. Pagani, J.H.; Zhao, M.; Cui, Z.; Avram, S.K.W.; Caruana, D.A.; Dudek, S.M.; Young, W.S. Role of the vasopressin 1b receptor in rodent aggressive behavior and synaptic plasticity in hippocampal area CA2. Mol. Psychiatry 2014, 20, 490–499.
  27. Cui, Z.; Gerfen, C.R.; Young, W.S., 3rd. Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus. J. Comp. Neurol. 2013, 521, 1844–1866.
  28. Zhang, L.; Hernández, V. Synaptic innervation to rat hippocampus by vasopressin-immuno-positive fibres from the hypothalamic supraoptic and paraventricular nuclei. Neuroscience 2013, 228, 139–162.
  29. Chen, S.; He, L.; Huang, A.J.Y.; Boehringer, R.; Robert, V.; Wintzer, M.E.; Polygalov, D.; Weitemier, A.Z.; Tao, Y.; Gu, M.; et al. A hypothalamic novelty signal modulates hippocampal memory. Nature 2020, 586, 270–274.
  30. Qin, H.; Fu, L.; Jian, T.; Jin, W.; Liang, M.; Li, J.; Chen, Q.; Yang, X.; Du, H.; Liao, X.; et al. REM sleep-active hypothalamic neurons may contribute to hippocampal social-memory consolidation. Neuron 2022, 110, 4000–4014.e6.
  31. Dasgupta, A.; Baby, N.; Krishna, K.; Hakim, M.; Wong, Y.P.; Behnisch, T.; Soong, T.W.; Sajikumar, S. Substance P induces plasticity and synaptic tagging/capture in rat hippocampal area CA2. Proc. Natl. Acad. Sci. USA 2017, 114, E8741–E8749.
  32. Berger, B.; Esclapez, M.; Alvarez, C.; Meyer, G.; Catala, M. Human and monkey fetal brain development of the supramammillary-hippocampal projections: A system involved in the regulation of theta activity. J. Comp. Neurol. 2000, 429, 515–529.
  33. Meira, T.; Leroy, F.; Buss, E.W.; Oliva, A.; Park, J.; Siegelbaum, S.A. A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics. Nat. Commun. 2018, 9, 4163.
  34. Leroy, F.; Brann, D.H.; Meira, T.; Siegelbaum, S.A. Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its Potential Role in Social Memory. Neuron 2017, 95, 1089–1102.e5.
  35. Alexander, G.M.; Brown, L.Y.; Farris, S.; Lustberg, D.; Pantazis, C.; Gloss, B.; Plummer, N.W.; Jensen, P.; Dudek, S.M. CA2 neuronal activity controls hippocampal low gamma and ripple oscillations. eLife. 2018, 7, e38052.
  36. Oliva, A.; Fernández-Ruiz, A.; Leroy, F.; Siegelbaum, S.A. Hippocampal CA2 sharp-wave ripples reactivate and promote social memory. Nature 2020, 587, 264–269.
  37. Srinivas, K.V.; Buss, E.W.; Sun, Q.; Santoro, B.; Takahashi, H.; Nicholson, D.A.; Siegelbaum, S.A. The Dendrites of CA2 and CA1 Pyramidal Neurons Differentially Regulate Information Flow in the Cortico-Hippocampal Circuit. J Neurosci. 2017, 37, 3276–3293.
  38. McCann, K.E.; Lustberg, D.J.; Shaughnessy, E.K.; Carstens, K.E.; Farris, S.; Alexander, G.M.; Radzicki, D.; Zhao, M.; Dudek, S.M. Novel role for mineralocorticoid receptors in control of a neuronal phenotype. Mol. Psychiatry 2019, 26, 350–364.
  39. Simons, S.B.; Caruana, D.A.; Zhao, M.; Dudek, S.M. Caffeine-induced synaptic potentiation in hippocampal CA2 neurons. Nat. Neurosci. 2011, 15, 23–25.
  40. Caruana, D.; Dudek, S.M. Adenosine A1 Receptor-Mediated Synaptic Depression in the Developing Hippocampal Area CA2. Front. Synaptic Neurosci. 2020, 12, 21.
  41. Bertoni, A.; Schaller, F.; Tyzio, R.; Gaillard, S.; Santini, F.; Xolin, M.; Diabira, D.; Vaidyanathan, R.; Matarazzo, V.; Medina, I.; et al. Oxytocin administration in neonates shapes hippocampal circuitry and restores social behavior in a mouse model of autism. Mol. Psychiatry 2021, 26, 7582–7595.
  42. Dasgupta, A.; Lim, Y.J.; Kumar, K.; Baby, N.; Pang, K.L.K.; Benoy, A.; Behnisch, T.; Sajikumar, S. Group III metabotropic glutamate receptors gate long-term potentiation and synaptic tagging/capture in rat hippocampal area CA2. eLife 2020, 9, 55344.
  43. Robert, V.; Therreau, L.; Davatolhagh, M.F.; Bernardo-Garcia, F.J.; Clements, K.N.; Chevaleyre, V.; Piskorowski, R.A. The mechanisms shaping CA2 pyramidal neuron action potential bursting induced by muscarinic acetylcholine receptor activation. J. Gen. Physiol. 2020, 152, 12462.
  44. Benoy, A.; Bin Ibrahim, M.Z.; Behnisch, T.; Sajikumar, S. Metaplastic Reinforcement of Long-Term Potentiation in Hippocampal Area CA2 by Cholinergic Receptor Activation. J. Neurosci. 2021, 41, 9082–9098.
  45. Nouraei, N.; Mason, D.M.; Miner, K.M.; Carcella, M.A.; Bhatia, T.N.; Dumm, B.K.; Soni, D.; Johnson, D.A.; Luk, K.C.; Leak, R.K. Critical appraisal of pathology transmission in the α-synuclein fibril model of Lewy body disorders. Exp. Neurol. 2017, 299, 172–196.
  46. Irwin, D.J.; Grossman, M.; Weintraub, D.; I Hurtig, H.; Duda, J.E.; Xie, S.X.; Lee, E.B.; Van Deerlin, V.M.; Lopez, O.L.; Kofler, J.K.; et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: A retrospective analysis. Lancet Neurol. 2017, 16, 55–65.
  47. Adamowicz, D.H.; Roy, S.; Salmon, D.P.; Galasko, D.R.; Hansen, L.A.; Masliah, E.; Gage, F.H. Hippocampal α-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology. J. Neurosci. 2016, 37, 1675–1684.
  48. Churchyard, A.; Lees, A.J. The relationship between dementia and direct involvement of the hippocampus and amygdala in Parkinson’s disease. Neurology 1997, 49, 1570–1576.
  49. Trudler, D.; Sanz-Blasco, S.; Eisele, Y.S.; Ghatak, S.; Bodhinathan, K.; Akhtar, M.W.; Lynch, W.P.; Piña-Crespo, J.C.; Talantova, M.; Kelly, J.W.; et al. α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss. J. Neurosci. 2021, 41, 2264–2273.
  50. Kalaitzakis, M.; Pearce, R.; Gentleman, S. Clinical correlates of pathology in the claustrum in Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 2009, 461, 12–15.
  51. Flores-Cuadrado, A.; Ubeda-Bañon, I.; Saiz-Sanchez, D.; de la Rosa-Prieto, C.; Martinez-Marcos, A. Hippocampal α-synuclein and interneurons in Parkinson’s disease: Data from human and mouse models. Mov. Disord. 2016, 31, 979–988.
  52. Maki, R.A.; Holzer, M.; Motamedchaboki, K.; Malle, E.; Masliah, E.; Marsche, G.; Reynolds, W.F. Human myeloperoxidase (hMPO) is expressed in neurons in the substantia nigra in Parkinson’s disease and in the hMPO-α-synuclein-A53T mouse model, correlating with increased nitration and aggregation of α-synuclein and exacerbation of motor impairment. Free. Radic. Biol. Med. 2019, 141, 115–140.
  53. Hall, H.; Reyes, S.; Landeck, N.; Bye, C.; Leanza, G.; Double, K.; Thompson, L.; Halliday, G.; Kirik, D. Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson’s disease. Brain 2014, 137, 2493–2508.
  54. Liu, A.K.L.; Chau, T.W.; Lim, E.J.; Ahmed, I.; Chang, R.C.-C.; Kalaitzakis, M.E.; Graeber, M.B.; Gentleman, S.M.; Pearce, R.K.B. Hippocampal CA2 Lewy pathology is associated with cholinergic degeneration in Parkinson’s disease with cognitive decline. Acta Neuropathol. Commun. 2019, 7, 61.
More
Information
Subjects: Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : ,
View Times: 172
Revisions: 2 times (View History)
Update Date: 27 Jul 2023
1000/1000