---
_id: '12809'
abstract:
- lang: eng
  text: "Understanding the mechanisms of learning and memory formation has always
    been one of\r\nthe main goals in neuroscience. Already Pavlov (1927) in his early
    days has used his classic\r\nconditioning experiments to study the neural mechanisms
    governing behavioral adaptation.\r\nWhat was not known back then was that the
    part of the brain that is largely responsible for\r\nthis type of associative
    learning is the cerebellum.\r\nSince then, plenty of theories on cerebellar learning
    have emerged. Despite their differences,\r\none thing they all have in common
    is that learning relies on synaptic and intrinsic plasticity.\r\nThe goal of my
    PhD project was to unravel the molecular mechanisms underlying synaptic\r\nplasticity
    in two synapses that have been shown to be implicated in motor learning, in an\r\neffort
    to understand how learning and memory formation are processed in the cerebellum.\r\nOne
    of the earliest and most well-known cerebellar theories postulates that motor
    learning\r\nlargely depends on long-term depression at the parallel fiber-Purkinje
    cell (PC-PC) synapse.\r\nHowever, the discovery of other types of plasticity in
    the cerebellar circuitry, like long-term\r\npotentiation (LTP) at the PC-PC synapse,
    potentiation of molecular layer interneurons (MLIs),\r\nand plasticity transfer
    from the cortex to the cerebellar/ vestibular nuclei has increased the\r\npopularity
    of the idea that multiple sites of plasticity might be involved in learning.\r\nStill
    a lot remains unknown about the molecular mechanisms responsible for these types
    of\r\nplasticity and whether they occur during physiological learning.\r\nIn the
    first part of this thesis we have analyzed the variation and nanodistribution
    of voltagegated calcium channels (VGCCs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
    acid\r\ntype glutamate receptors (AMPARs) on the parallel fiber-Purkinje cell
    synapse after vestibuloocular reflex phase reversal adaptation, a behavior that
    has been suggested to rely on PF-PC\r\nLTP. We have found that on the last day
    of adaptation there is no learning trace in form of\r\nVGCCs nor AMPARs variation
    at the PF-PC synapse, but instead a decrease in the number of\r\nPF-PC synapses.
    These data seem to support the view that learning is only stored in the\r\ncerebellar
    cortex in an initial learning phase, being transferred later to the vestibular
    nuclei.\r\nNext, we have studied the role of MLIs in motor learning using a relatively
    simple and well characterized behavioral paradigm – horizontal optokinetic reflex
    (HOKR) adaptation. We\r\nhave found behavior-induced MLI potentiation in form
    of release probability increase that\r\ncould be explained by the increase of
    VGCCs at the presynaptic side. Our results strengthen\r\nthe idea of distributed
    cerebellar plasticity contributing to learning and provide a novel\r\nmechanism
    for release probability increase. "
acknowledged_ssus:
- _id: EM-Fac
- _id: Bio
- _id: PreCl
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Catarina
  full_name: Alcarva, Catarina
  id: 3A96634C-F248-11E8-B48F-1D18A9856A87
  last_name: Alcarva
citation:
  ama: 'Alcarva C. Plasticity in the cerebellum: What molecular mechanisms are behind
    physiological learning. 2023. doi:<a href="https://doi.org/10.15479/at:ista:12809">10.15479/at:ista:12809</a>'
  apa: 'Alcarva, C. (2023). <i>Plasticity in the cerebellum: What molecular mechanisms
    are behind physiological learning</i>. Institute of Science and Technology Austria.
    <a href="https://doi.org/10.15479/at:ista:12809">https://doi.org/10.15479/at:ista:12809</a>'
  chicago: 'Alcarva, Catarina. “Plasticity in the Cerebellum: What Molecular Mechanisms
    Are behind Physiological Learning.” Institute of Science and Technology Austria,
    2023. <a href="https://doi.org/10.15479/at:ista:12809">https://doi.org/10.15479/at:ista:12809</a>.'
  ieee: 'C. Alcarva, “Plasticity in the cerebellum: What molecular mechanisms are
    behind physiological learning,” Institute of Science and Technology Austria, 2023.'
  ista: 'Alcarva C. 2023. Plasticity in the cerebellum: What molecular mechanisms
    are behind physiological learning. Institute of Science and Technology Austria.'
  mla: 'Alcarva, Catarina. <i>Plasticity in the Cerebellum: What Molecular Mechanisms
    Are behind Physiological Learning</i>. Institute of Science and Technology Austria,
    2023, doi:<a href="https://doi.org/10.15479/at:ista:12809">10.15479/at:ista:12809</a>.'
  short: 'C. Alcarva, Plasticity in the Cerebellum: What Molecular Mechanisms Are
    behind Physiological Learning, Institute of Science and Technology Austria, 2023.'
date_created: 2023-04-06T07:54:09Z
date_published: 2023-04-06T00:00:00Z
date_updated: 2023-04-26T12:16:56Z
day: '06'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: GradSch
- _id: RySh
doi: 10.15479/at:ista:12809
file:
- access_level: closed
  checksum: 35b5997d2b0acb461f9d33d073da0df5
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  date_updated: 2023-04-07T06:16:06Z
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  creator: cchlebak
  date_created: 2023-04-07T06:18:05Z
  date_updated: 2023-04-07T06:18:05Z
  file_id: '12816'
  file_name: Thesis_CatarinaAlcarva_final.docx
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  relation: source_file
file_date_updated: 2023-04-07T06:18:05Z
has_accepted_license: '1'
language:
- iso: eng
month: '04'
oa_version: Published Version
page: '115'
project:
- _id: 267DFB90-B435-11E9-9278-68D0E5697425
  name: 'Plasticity in the cerebellum: Which molecular mechanisms are behind physiological
    learning?'
publication_identifier:
  issn:
  - 2663 - 337X
publication_status: published
publisher: Institute of Science and Technology Austria
status: public
supervisor:
- first_name: Ryuichi
  full_name: Shigemoto, Ryuichi
  id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
  last_name: Shigemoto
  orcid: 0000-0001-8761-9444
title: 'Plasticity in the cerebellum: What molecular mechanisms are behind physiological
  learning'
type: dissertation
user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9
year: '2023'
...
---
_id: '11393'
abstract:
- lang: eng
  text: "AMPA receptors (AMPARs) mediate fast excitatory neurotransmission and their
    role is\r\nimplicated in complex processes such as learning and memory and various
    neurological\r\ndiseases. These receptors are composed of different subunits and
    the subunit composition can\r\naffect channel properties, receptor trafficking
    and interaction with other associated proteins.\r\nUsing the high sensitivity
    SDS-digested freeze-fracture replica labeling (SDS-FRL) for\r\nelectron microscopy
    I investigated the number, density, and localization of AMPAR subunits,\r\nGluA1,
    GluA2, GluA3, and GluA1-3 (panAMPA) in pyramidal cells in the CA1 area of mouse\r\nhippocampus.
    I have found that the immunogold labeling for all of these subunits in the\r\npostsynaptic
    sites was highest in stratum radiatum and lowest in stratum lacunosummoleculare.
    The labeling density for the all subunits in the extrasynaptic sites showed a
    gradual\r\nincrease from the pyramidal cell soma towards the distal part of stratum
    radiatum. The densities\r\nof extrasynaptic GluA1, GluA2 and panAMPA labeling
    reached 10-15% of synaptic densities,\r\nwhile the ratio of extrasynaptic labeling
    for GluA3 was significantly lower compared than those\r\nfor other subunits. The
    labeling patterns for GluA1, GluA2 and GluA1-3 are similar and their\r\ndensities
    were higher in the periphery than center of synapses. In contrast, the GluA3-\r\ncontaining
    receptors were more centrally localized compared to the GluA1- and GluA2-\r\ncontaining
    receptors.\r\nThe hippocampus plays a central role in learning and memory. Contextual
    learning has been\r\nshown to require the delivery of AMPA receptors to CA1 synapses
    in the dorsal hippocampus.\r\nHowever, proximodistal heterogeneity of this plasticity
    and particular contribution of different\r\nAMPA receptor subunits are not fully
    understood. By combining inhibitory avoidance task, a\r\nhippocampus-dependent
    contextual fear-learning paradigm, with SDS-FRL, I have revealed an\r\nincrease
    in synaptic density specific to GluA1-containing AMPA receptors in the CA1 area.\r\nThe
    intrasynaptic distribution of GluA1 also changed from the periphery to center-preferred\r\npattern.
    Furthermore, this synaptic plasticity was evident selectively in stratum radiatum
    but\r\nnot stratum oriens, and in the CA1 subregion proximal but not distal to
    CA2. These findings\r\nfurther contribute to our understanding of how specific
    hippocampal subregions and AMPA\r\nreceptor subunits are involved in physiological
    learning.\r\nAlthough the immunolabeling results above shed light on subunit-specific
    plasticity in\r\nAMPAR distribution, no tools to visualize and study the subunit
    composition at the single\r\nchannel level in situ have been available. Electron
    microscopy with conventional immunogold\r\nlabeling approaches has limitations
    in the single channel analysis because of the large size of\r\nantibodies and
    steric hindrance hampering multiple subunit labeling of single channels. I\r\nmanaged
    to develop a new chemical labeling system using a short peptide tag and small\r\nsynthetic
    probes, which form specific covalent bond with a cysteine residue in the tag fused
    to\r\nproteins of interest (reactive tag system). I additionally made substantial
    progress into adapting\r\nthis system for AMPA receptor subunits."
acknowledged_ssus:
- _id: EM-Fac
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Marijo
  full_name: Jevtic, Marijo
  id: 4BE3BC94-F248-11E8-B48F-1D18A9856A87
  last_name: Jevtic
citation:
  ama: Jevtic M. Contextual fear learning induced changes in AMPA receptor subtypes
    along the proximodistal axis in dorsal hippocampus. 2022. doi:<a href="https://doi.org/10.15479/at:ista:11393">10.15479/at:ista:11393</a>
  apa: Jevtic, M. (2022). <i>Contextual fear learning induced changes in AMPA receptor
    subtypes along the proximodistal axis in dorsal hippocampus</i>. Institute of
    Science and Technology Austria. <a href="https://doi.org/10.15479/at:ista:11393">https://doi.org/10.15479/at:ista:11393</a>
  chicago: Jevtic, Marijo. “Contextual Fear Learning Induced Changes in AMPA Receptor
    Subtypes along the Proximodistal Axis in Dorsal Hippocampus.” Institute of Science
    and Technology Austria, 2022. <a href="https://doi.org/10.15479/at:ista:11393">https://doi.org/10.15479/at:ista:11393</a>.
  ieee: M. Jevtic, “Contextual fear learning induced changes in AMPA receptor subtypes
    along the proximodistal axis in dorsal hippocampus,” Institute of Science and
    Technology Austria, 2022.
  ista: Jevtic M. 2022. Contextual fear learning induced changes in AMPA receptor
    subtypes along the proximodistal axis in dorsal hippocampus. Institute of Science
    and Technology Austria.
  mla: Jevtic, Marijo. <i>Contextual Fear Learning Induced Changes in AMPA Receptor
    Subtypes along the Proximodistal Axis in Dorsal Hippocampus</i>. Institute of
    Science and Technology Austria, 2022, doi:<a href="https://doi.org/10.15479/at:ista:11393">10.15479/at:ista:11393</a>.
  short: M. Jevtic, Contextual Fear Learning Induced Changes in AMPA Receptor Subtypes
    along the Proximodistal Axis in Dorsal Hippocampus, Institute of Science and Technology
    Austria, 2022.
date_created: 2022-05-17T08:57:41Z
date_published: 2022-05-16T00:00:00Z
date_updated: 2023-09-07T14:53:44Z
day: '16'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: GradSch
- _id: RySh
doi: 10.15479/at:ista:11393
file:
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  checksum: 8fc695d88020d70d231dad0e9f10b138
  content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document
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  date_created: 2022-05-17T09:08:06Z
  date_updated: 2023-05-17T22:30:03Z
  embargo_to: open_access
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  file_name: MJ thesis.docx
  file_size: 56427603
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  date_updated: 2023-05-17T22:30:03Z
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file_date_updated: 2023-05-17T22:30:03Z
has_accepted_license: '1'
language:
- iso: eng
month: '05'
oa: 1
oa_version: Published Version
page: '108'
publication_identifier:
  issn:
  - 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
  record:
  - id: '7391'
    relation: part_of_dissertation
    status: public
status: public
supervisor:
- first_name: Ryuichi
  full_name: Shigemoto, Ryuichi
  id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
  last_name: Shigemoto
  orcid: 0000-0001-8761-9444
title: Contextual fear learning induced changes in AMPA receptor subtypes along the
  proximodistal axis in dorsal hippocampus
type: dissertation
user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9
year: '2022'
...
---
_id: '9562'
abstract:
- lang: eng
  text: Left-right asymmetries can be considered a fundamental organizational principle
    of the vertebrate central nervous system. The hippocampal CA3-CA1 pyramidal cell
    synaptic connection shows an input-side dependent asymmetry where the hemispheric
    location of the presynaptic CA3 neuron determines the synaptic properties. Left-input
    synapses terminating on apical dendrites in stratum radiatum have a higher density
    of NMDA receptor subunit GluN2B, a lower density of AMPA receptor subunit GluA1
    and smaller areas with less often perforated PSDs. On the other hand, left-input
    synapses terminating on basal dendrites in stratum oriens have lower GluN2B densities
    than right-input ones. Apical and basal synapses further employ different signaling
    pathways involved in LTP. SDS-digested freeze-fracture replica labeling can visualize
    synaptic membrane proteins with high sensitivity and resolution, and has been
    used to reveal the asymmetry at the electron microscopic level. However, it requires
    time-consuming manual demarcation of the synaptic surface for quantitative measurements.
    To facilitate the analysis of replica labeling, I first developed a software named
    Darea, which utilizes deep-learning to automatize this demarcation. With Darea
    I characterized the synaptic distribution of NMDA and AMPA receptors as well as
    the voltage-gated Ca2+ channels in CA1 stratum radiatum and oriens. Second, I
    explored the role of GluN2B and its carboxy-terminus in the establishment of input-side
    dependent hippocampal asymmetry. In conditional knock-out mice lacking GluN2B
    expression in CA1 and GluN2B-2A swap mice, where GluN2B carboxy-terminus was exchanged
    to that of GluN2A, no significant asymmetries of GluN2B, GluA1 and PSD area were
    detected. We further discovered a previously unknown functional asymmetry of GluN2A,
    which was also lost in the swap mouse. These results demonstrate that GluN2B carboxy-terminus
    plays a critical role in normal formation of input-side dependent asymmetry.
acknowledged_ssus:
- _id: EM-Fac
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: David
  full_name: Kleindienst, David
  id: 42E121A4-F248-11E8-B48F-1D18A9856A87
  last_name: Kleindienst
citation:
  ama: 'Kleindienst D. 2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor
    subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning.
    2021. doi:<a href="https://doi.org/10.15479/at:ista:9562">10.15479/at:ista:9562</a>'
  apa: 'Kleindienst, D. (2021). <i>2B or not 2B: Hippocampal asymmetries mediated
    by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis
    by Deep-Learning</i>. Institute of Science and Technology Austria. <a href="https://doi.org/10.15479/at:ista:9562">https://doi.org/10.15479/at:ista:9562</a>'
  chicago: 'Kleindienst, David. “2B or Not 2B: Hippocampal Asymmetries Mediated by
    NMDA Receptor Subunit GluN2B C-Terminus and High-Throughput Image Analysis by
    Deep-Learning.” Institute of Science and Technology Austria, 2021. <a href="https://doi.org/10.15479/at:ista:9562">https://doi.org/10.15479/at:ista:9562</a>.'
  ieee: 'D. Kleindienst, “2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor
    subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning,”
    Institute of Science and Technology Austria, 2021.'
  ista: 'Kleindienst D. 2021. 2B or not 2B: Hippocampal asymmetries mediated by NMDA
    receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning.
    Institute of Science and Technology Austria.'
  mla: 'Kleindienst, David. <i>2B or Not 2B: Hippocampal Asymmetries Mediated by NMDA
    Receptor Subunit GluN2B C-Terminus and High-Throughput Image Analysis by Deep-Learning</i>.
    Institute of Science and Technology Austria, 2021, doi:<a href="https://doi.org/10.15479/at:ista:9562">10.15479/at:ista:9562</a>.'
  short: 'D. Kleindienst, 2B or Not 2B: Hippocampal Asymmetries Mediated by NMDA Receptor
    Subunit GluN2B C-Terminus and High-Throughput Image Analysis by Deep-Learning,
    Institute of Science and Technology Austria, 2021.'
date_created: 2021-06-17T14:10:47Z
date_published: 2021-06-01T00:00:00Z
date_updated: 2023-09-11T12:55:53Z
day: '01'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: GradSch
- _id: RySh
doi: 10.15479/at:ista:9562
file:
- access_level: open_access
  checksum: 659df5518db495f679cb1df9e9bd1d94
  content_type: application/pdf
  creator: dkleindienst
  date_created: 2021-06-17T14:03:14Z
  date_updated: 2022-07-02T22:30:04Z
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  file_name: Thesis.pdf
  file_size: 77299142
  relation: main_file
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  checksum: 3bcf63a2b19e5b6663be051bea332748
  content_type: application/zip
  creator: dkleindienst
  date_created: 2021-06-17T14:04:30Z
  date_updated: 2022-07-02T22:30:04Z
  embargo_to: open_access
  file_id: '9564'
  file_name: Thesis_source.zip
  file_size: 369804895
  relation: source_file
file_date_updated: 2022-07-02T22:30:04Z
has_accepted_license: '1'
language:
- iso: eng
month: '06'
oa: 1
oa_version: Published Version
page: '124'
publication_identifier:
  issn:
  - 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
  record:
  - id: '9756'
    relation: part_of_dissertation
    status: public
  - id: '9437'
    relation: part_of_dissertation
    status: public
  - id: '8532'
    relation: part_of_dissertation
    status: public
  - id: '612'
    relation: part_of_dissertation
    status: public
status: public
supervisor:
- first_name: Ryuichi
  full_name: Shigemoto, Ryuichi
  id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
  last_name: Shigemoto
  orcid: 0000-0001-8761-9444
title: '2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B
  C-terminus and high-throughput image analysis by Deep-Learning'
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2021'
...
---
_id: '7525'
abstract:
- lang: eng
  text: "The medial habenula (MHb) is an evolutionary conserved epithalamic structure
    important for the modulation of emotional memory. It is involved in regulation
    of anxiety, compulsive behavior, addiction (nicotinic and opioid), sexual and
    feeding behavior. MHb receives inputs from septal regions and projects exclusively
    to the interpeduncular nucleus (IPN). Distinct sub-regions of the septum project
    to different subnuclei of MHb: the bed nucleus of anterior commissure projects
    to dorsal MHb and the triangular septum projects to ventral MHb. Furthermore,
    the dorsal and ventral MHb project to the lateral and rostral/central IPN, respectively.
    Importantly, these projections have unique features of prominent co-release of
    different neurotransmitters and requirement of a peculiar type of calcium channel
    for release. In general, synaptic neurotransmission requires an activity-dependent
    influx of Ca2+ into the presynaptic terminal through voltage-gated calcium channels.
    The calcium channel family most commonly involved in neurotransmitter release
    comprises three members, P/Q-, N- and R-type with Cav2.1, Cav2.2 and Cav2.3 subunits,
    respectively. In contrast to most CNS synapses that mainly express Cav2.1 and/or
    Cav2.2, MHb terminals in the IPN exclusively express Cav2.3. In other parts of
    the brain, such as the hippocampus, Cav2.3 is mostly located to postsynaptic elements.
    This unusual presynaptic location of Cav2.3 in the MHb-IPN pathway implies unique
    mechanisms of glutamate release in this pathway. One potential example of such
    uniqueness is the facilitation of release by GABAB receptor (GBR) activation.
    Presynaptic GBRs usually inhibit the release of neurotransmitters by inhibiting
    presynaptic calcium channels. MHb shows the highest expression levels of GBR in
    the brain. GBRs comprise two subunits, GABAB1 (GB1) and GABAB2 (GB2), and are
    associated with auxiliary subunits, called potassium channel tetramerization domain
    containing proteins (KCTD) 8, 12, 12b and 16. Among these four subunits, KCTD12b
    is exclusively expressed in ventral MHb, and KCTD8 shows the strongest expression
    in the whole MHb among other brain regions, indicating that KCTD8 and KCTD12b
    may be involved in the unique mechanisms of neurotransmitter release mediated
    by Cav2.3 and regulated by GBRs in this pathway. \r\nIn the present study, we
    first verified that neurotransmission in both dorsal and ventral MHb-IPN pathways
    is mainly mediated by Cav2.3 using a selective blocker of R-type channels, SNX-482.
    We next found that baclofen, a GBR agonist, has facilitatory effects on release
    from ventral MHb terminal in rostral IPN, whereas it has inhibitory effects on
    release from dorsal MHb terminals in lateral IPN, indicating that KCTD12b expressed
    exclusively in ventral MHb may have a role in the facilitatory effects of GBR
    activation. In a heterologous expression system using HEK cells, we found that
    KCTD8 and KCTD12b but not KCTD12 directly bind with Cav2.3. Pre-embedding immunogold
    electron microscopy data show that Cav2.3 and KCTD12b are distributed most densely
    in presynaptic active zone in IPN with KCTD12b being present only in rostral/central
    but not lateral IPN, whereas GABAB, KCTD8 and KCTD12 are distributed most densely
    in perisynaptic sites with KCTD12 present more frequently in postsynaptic elements
    and only in rostral/central IPN. In freeze-fracture replica labelling, Cav2.3,
    KCTD8 and KCTD12b are co-localized with each other in the same active zone indicating
    that they may form complexes regulating vesicle release in rostral IPN. \r\nOn
    electrophysiological studies of wild type (WT) mice, we found that paired-pulse
    ratio in rostral IPN of KCTD12b knock-out (KO) mice is lower than those of WT
    and KCTD8 KO mice. Consistent with this finding, in mean variance analysis, release
    probability in rostral IPN of KCTD12b KO mice is higher than that of WT and KCTD8
    KO mice. Although paired-pulse ratios are not different between WT and KCTD8 KO
    mice, the mean variance analysis revealed significantly lower release probability
    in rostral IPN of KCTD8 KO than WT mice. These results demonstrate bidirectional
    regulation of Cav2.3-mediated release by KCTD8 and KCTD12b without GBR activation
    in rostral IPN. Finally, we examined the baclofen effects in rostral IPN of KCTD8
    and KCTD12b KO mice, and found the facilitation of release remained in both KO
    mice, indicating that the peculiar effects of the GBR activation in this pathway
    do not depend on the selective expression of these KCTD subunits in ventral MHb.
    However, we found that presynaptic potentiation of evoked EPSC amplitude by baclofen
    falls to baseline after washout faster in KCTD12b KO mice than WT, KCTD8 KO and
    KCTD8/12b double KO mice. This result indicates that KCTD12b is involved in sustained
    potentiation of vesicle release by GBR activation, whereas KCTD8 is involved in
    its termination in the absence of KCTD12b. Consistent with these functional findings,
    replica labelling revealed an increase in density of KCTD8, but not Cav2.3 or
    GBR at active zone in rostral IPN of KCTD12b KO mice compared with that of WT
    mice, suggesting that increased association of KCTD8 with Cav2.3 facilitates the
    release probability and termination of the GBR effect in the absence of KCTD12b.\r\nIn
    summary, our study provided new insights into the physiological roles of presynaptic
    Cav2.3, GBRs and their auxiliary subunits KCTDs at an evolutionary conserved neuronal
    circuit. Future studies will be required to identify the exact molecular mechanism
    underlying the GBR-mediated presynaptic potentiation on ventral MHb terminals.
    It remains to be determined whether the prominent presence of presynaptic KCTDs
    at active zone could exert similar neuromodulatory functions in different pathways
    of the brain.\r\n"
acknowledged_ssus:
- _id: EM-Fac
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Pradeep
  full_name: Bhandari, Pradeep
  id: 45EDD1BC-F248-11E8-B48F-1D18A9856A87
  last_name: Bhandari
  orcid: 0000-0003-0863-4481
citation:
  ama: Bhandari P. Localization and functional role of Cav2.3 in the medial habenula
    to interpeduncular nucleus pathway. 2020. doi:<a href="https://doi.org/10.15479/AT:ISTA:7525">10.15479/AT:ISTA:7525</a>
  apa: Bhandari, P. (2020). <i>Localization and functional role of Cav2.3 in the medial
    habenula to interpeduncular nucleus pathway</i>. Institute of Science and Technology
    Austria. <a href="https://doi.org/10.15479/AT:ISTA:7525">https://doi.org/10.15479/AT:ISTA:7525</a>
  chicago: Bhandari, Pradeep. “Localization and Functional Role of Cav2.3 in the Medial
    Habenula to Interpeduncular Nucleus Pathway.” Institute of Science and Technology
    Austria, 2020. <a href="https://doi.org/10.15479/AT:ISTA:7525">https://doi.org/10.15479/AT:ISTA:7525</a>.
  ieee: P. Bhandari, “Localization and functional role of Cav2.3 in the medial habenula
    to interpeduncular nucleus pathway,” Institute of Science and Technology Austria,
    2020.
  ista: Bhandari P. 2020. Localization and functional role of Cav2.3 in the medial
    habenula to interpeduncular nucleus pathway. Institute of Science and Technology
    Austria.
  mla: Bhandari, Pradeep. <i>Localization and Functional Role of Cav2.3 in the Medial
    Habenula to Interpeduncular Nucleus Pathway</i>. Institute of Science and Technology
    Austria, 2020, doi:<a href="https://doi.org/10.15479/AT:ISTA:7525">10.15479/AT:ISTA:7525</a>.
  short: P. Bhandari, Localization and Functional Role of Cav2.3 in the Medial Habenula
    to Interpeduncular Nucleus Pathway, Institute of Science and Technology Austria,
    2020.
date_created: 2020-02-26T10:56:37Z
date_published: 2020-02-28T00:00:00Z
date_updated: 2023-09-07T13:20:03Z
day: '28'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: RySh
doi: 10.15479/AT:ISTA:7525
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  title: Localization and functional role of Cav2.3 in the medial habenula to interpeduncular
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file_date_updated: 2021-03-01T23:30:04Z
has_accepted_license: '1'
keyword:
- Cav2.3
- medial habenula (MHb)
- interpeduncular nucleus (IPN)
language:
- iso: eng
month: '02'
oa: 1
oa_version: Published Version
page: '79'
publication_identifier:
  issn:
  - 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
status: public
supervisor:
- first_name: Ryuichi
  full_name: Shigemoto, Ryuichi
  id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
  last_name: Shigemoto
  orcid: 0000-0001-8761-9444
title: Localization and functional role of Cav2.3 in the medial habenula to interpeduncular
  nucleus pathway
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2020'
...
---
_id: '51'
abstract:
- lang: eng
  text: Asymmetries have long been known about in the central nervous system. From
    gross anatomical differences, such as the presence of the parapineal organ in
    only one hemisphere of the developing zebrafish, to more subtle differences in
    activity between both hemispheres, as seen in freely roaming animals or human
    participants under PET and fMRI imaging analysis. The presence of asymmetries
    has been demonstrated to have huge behavioural implications, with their disruption
    often leading to the generation of neurological disorders, memory problems, changes
    in personality, and in an organism's health and well-being. For my Ph.D. work
    I aimed to tackle two important avenues of research. The first being the process
    of input-side dependency in the hippocampus, with the goal of finding a key gene
    responsible for its development (Gene X). The second project was to do with experience-induced
    laterality formation in the hippocampus. Specifically, how laterality in the synapse
    density of the CA1 stratum radiatum (s.r.) could be induced purely through environmental
    enrichment. Through unilateral tracer injections into the CA3, I was able to selectively
    measure the properties of synapses within the CA1 and investigate how they differed
    based upon which hemisphere the presynaptic neurone originated. Having found the
    existence of a previously unreported reversed (left-isomerism) i.v. mutant, through
    morpholocal examination of labelled terminals in the CA1 s.r., I aimed to elucidate
    a key gene responsible for the process of left or right determination of inputs
    to the CA1 s.r.. This work relates to the previous finding of input-side dependent
    asymmetry in the wild-type rodent, where the origin of the projecting neurone
    to the CA1 will determine the morphology of a synapse, to a greater degree than
    the hemisphere in which the projection terminates. Using left- and right-isomerism
    i.v. mice, in combination with whole genome sequence analysis, I highlight Ena/VASP-like
    (Evl) as a potential target for Gene X. In relation to this topic, I also highlight
    my work in the recently published paper of how knockout of PirB can lead to a
    lack of input-side dependency in the murine hippocampus. For the second question,
    I show that the environmental enrichment paradigm will lead to an asymmetry in
    the synapse densities in the hippocampus of mice. I also highlight that the nature
    of the enrichment is of less consequence than the process of enrichment itself.
    I demonstrate that the CA3 region will dramatically alter its projection targets,
    in relation to environmental stimulation, with the asymmetry in synaptic density,
    caused by enrichment, relying heavily on commissural fibres. I also highlight
    the vital importance of input-side dependent asymmetry, as a necessary component
    of experience-dependent laterality formation in the CA1 s.r.. However, my results
    suggest that it isn't the only cause, as there appears to be a CA1 dependent mechanism
    also at play. Upon further investigation, I highlight the significant, and highly
    important, finding that the changes seen in the CA1 s.r. were predominantly caused
    through projections from the left-CA3, with the right-CA3 having less involvement
    in this mechanism.
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Matthew J
  full_name: Case, Matthew J
  id: 44B7CA5A-F248-11E8-B48F-1D18A9856A87
  last_name: Case
citation:
  ama: 'Case MJ. From the left to the right: A tale of asymmetries, environments,
    and hippocampal development. 2018. doi:<a href="https://doi.org/10.15479/AT:ISTA:th_1032">10.15479/AT:ISTA:th_1032</a>'
  apa: 'Case, M. J. (2018). <i>From the left to the right: A tale of asymmetries,
    environments, and hippocampal development</i>. Institute of Science and Technology
    Austria. <a href="https://doi.org/10.15479/AT:ISTA:th_1032">https://doi.org/10.15479/AT:ISTA:th_1032</a>'
  chicago: 'Case, Matthew J. “From the Left to the Right: A Tale of Asymmetries, Environments,
    and Hippocampal Development.” Institute of Science and Technology Austria, 2018.
    <a href="https://doi.org/10.15479/AT:ISTA:th_1032">https://doi.org/10.15479/AT:ISTA:th_1032</a>.'
  ieee: 'M. J. Case, “From the left to the right: A tale of asymmetries, environments,
    and hippocampal development,” Institute of Science and Technology Austria, 2018.'
  ista: 'Case MJ. 2018. From the left to the right: A tale of asymmetries, environments,
    and hippocampal development. Institute of Science and Technology Austria.'
  mla: 'Case, Matthew J. <i>From the Left to the Right: A Tale of Asymmetries, Environments,
    and Hippocampal Development</i>. Institute of Science and Technology Austria,
    2018, doi:<a href="https://doi.org/10.15479/AT:ISTA:th_1032">10.15479/AT:ISTA:th_1032</a>.'
  short: 'M.J. Case, From the Left to the Right: A Tale of Asymmetries, Environments,
    and Hippocampal Development, Institute of Science and Technology Austria, 2018.'
date_created: 2018-12-11T11:44:22Z
date_published: 2018-06-27T00:00:00Z
date_updated: 2023-09-07T12:39:22Z
day: '27'
ddc:
- '571'
- '576'
degree_awarded: PhD
department:
- _id: RySh
doi: 10.15479/AT:ISTA:th_1032
file:
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  date_created: 2019-04-09T07:16:26Z
  date_updated: 2021-02-11T23:30:13Z
  embargo_to: open_access
  file_id: '6251'
  file_name: 2018_Thesis_Case_Source.doc
  file_size: 141270528
  relation: source_file
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  date_created: 2019-04-09T07:16:23Z
  date_updated: 2021-02-11T11:17:14Z
  embargo: 2019-07-05
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  file_size: 15193621
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file_date_updated: 2021-02-11T23:30:13Z
has_accepted_license: '1'
language:
- iso: eng
month: '06'
oa: 1
oa_version: Published Version
page: '186'
publication_identifier:
  issn:
  - 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
publist_id: '8003'
pubrep_id: '1032'
related_material:
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  - id: '682'
    relation: part_of_dissertation
    status: public
status: public
supervisor:
- first_name: Ryuichi
  full_name: Shigemoto, Ryuichi
  id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
  last_name: Shigemoto
  orcid: 0000-0001-8761-9444
title: 'From the left to the right: A tale of asymmetries, environments, and hippocampal
  development'
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2018'
...