High precision is critical for normal neural circuit function, but that precision is not
innate. The location, strength, and number of inputs in a neural circuit are
modified in early postnatal development in a process called refinement. The
refinement of long-range excitatory projections is well-known, but less is known
about the refinement of long-range inhibitory projections. What we do know about
inhibitory projection refinement comes from the glycinergic medial nucleus to the
trapezoid body to lateral superior olive (MNTB-LSO) projection of the auditory
brainstem. During early postnatal life, the MNTB-LSO projection undergoes
morphological and physiological refinement. Notably, the MNTB-LSO projection
transiently expresses vesicular glutamate transporter 3 (VGLUT3) and
synaptotagmin 1 (Syt1), transiently releases glutamate, and undergoes
glutamate-dependent refinement. However, it remains uncertain whether
glutamate release is specific to the auditory brainstem or could be a more
general phenomenon of inhibitory projections.
To shed light on this question, I investigated another inhibitory projection of the
hindbrain, the GABAergic Purkinje projection of the cerebellum. The Purkinje
projection shares key characteristics with the MNTB-LSO projection, including its
inhibitory nature, location in the hindbrain, obvious topographic organization,
heterogeneity of the target cells, and expression of VGLUT3 transcript and
protein. In this thesis, I sought to determine: 1) whether the expression profile of
VGLUT3 and Syt1 in the Purkinje projection matches that of the MNTB-LSO
projection, and whether the Purkinje projection also releases glutamate, 2)
whether the expression profile of synaptic vesicle protein 2 (SV2) isoforms, SV2B
and SV2C, matches the expression profile of other synaptic vesicle proteins in
the Purkinje and MNTB-LSO projection, and 3) whether the Purkinje projection
undergoes postnatal morphological refinement like the MNTB-LSO projection. I
found that like the MNTB-LSO projection, the Purkinje projection transiently
expresses VGLUT3 and Syt1, releases glutamate in early postnatal life, and may
undergo morphological refinement. / Dissertation / Doctor of Philosophy (PhD) / Everything you do, whether it be playing your favorite sport or begrudgingly
reading this thesis, requires neural circuits, which are the basic functional unit of
the nervous system. How neurons are wired together is crucial for their role in
executing a task. But how these neurons fine-tune their connections – in a
process called refinement, by getting the right connections to the right location, of
the right strength, and of the right number – is an open-ended question in
neuroscience. Refinement is more well-studied in excitatory projection neurons,
but we know very little about how refinement occurs in inhibitory projection
neurons. I compare some of the unusual characteristics of what we do know
about inhibitory refinement in the auditory brainstem to another famous projection
of the hindbrain, the Purkinje projection. Understanding more about the
refinement of inhibitory projections gives key insights into how neural circuits
function and how they facilitate complex behaviours.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/29081 |
| Date | January 2023 |
| Creators | Simon, Shane Joseph |
| Contributors | Gillespie, Deda C, Health Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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