| dc.contributor.advisor | Loewel, Siegrid Prof. Dr. | |
| dc.contributor.author | Stodieck, Sophia Katharina | |
| dc.date.accessioned | 2017-09-25T11:54:56Z | |
| dc.date.available | 2017-09-25T11:54:56Z | |
| dc.date.issued | 2017-09-25 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0023-3F15-A | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-6478 | |
| dc.language.iso | eng | de |
| dc.relation.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | The role of postsynaptic density (PSD) proteins PSD-95 and PSD-93 for mouse visual cortical plasticity and vision | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Loewel, Siegrid Prof. Dr. | |
| dc.date.examination | 2016-09-26 | |
| dc.description.abstracteng | During neurodevelopment in the brain, several changes including structural, molecular and
functional changes take place in order to promote its maturation. These changes occur at
multiple levels, with modifications in synaptic transmission, protein expression or the
sensitivity to experience-dependent plasticity. In mice, ocular dominance (OD) plasticity is
highest during the critical period (CP) between postnatal days (P) 20 – P 35 and decreases
afterwards until it is fully absent in mice > P 110 when raised in standard cages.
The predominant view is that excitation and inhibition are the key players in opening and
closing the CP. The present PhD thesis proposes a different mechanism which is based upon
the two postsynaptic density proteins (PSD) 93 and 95 of the membrane associated guanylate
kinase (MAGUK) protein family. Both scaffold proteins are required for organization of
postsynaptic signaling and synaptic transmission in excitatory synapses. PSD-95 was shown
to be absolutely required for experience-dependent maturation of AMPA receptor silent
synapses in the visual cortex (VC) of mice, whereas PSD-93 might act as an opponent and
prevents early synaptic maturation.
To assess the contribution of both proteins in OD-plasticity, PSD-95 and PSD-93 knockout (KO)
mice were examined by using monocular deprivation (MD) and optical imaging of intrinsic
signals in vivo. In addition, visual abilities of these mice were analyzed with the behavioral
tests optomotor system and the visual water task (VWT). PSD-95 KO mice show lifelong
juvenile-like OD-plasticity after both 4 and 7 days (d) of MD at least until P 507. Furthermore,
pharmacological manipulation of enhancing intracortical inhibition in vivo resulted in juvenilelike
OD-plasticity in PSD-95 KO while it was completely prevented in WT mice (< P 110). This
suggests that the preserved OD-plasticity in PSD-95 KO mice is caused by a higher fraction of
AMPA receptor silent synapses. Under consideration of the generally unstable nature of
PSD-95 deficient neurons, a modified OD-plasticity paradigm was designed: After 7 d of MD,
the previously deprived eye was reopened and recovery time of the induced OD- shift was
significantly increased (2 d) in PSD-95 KO mice compared to WT. Thus, plastic changes in PSD-
95 KO mice are more transient and reverse faster than in WT mice. This indicates that synaptic
changes during experience-dependent network refinements cannot be consolidated and
functional properties of neurons may not be stabilized without PSD-95.
To narrow down the exact location of OD-plasticity expression, a VC-restricted knockdown(KD) of PSD-95 was conducted in P 0, P 40 or > P 140 WT mice. OD-plasticity was present after
4 d of MD in all tested KD animals and the location of its expression is confined to the
contralateral VC of the deprived eye. Together, these results support a conceptual model of
PSD-95-dependent silent synapse maturation which eventually leads to the ending of the CP
for OD-plasticity.
Contemporaneously to this project, a KO of PSD-93 was shown to evoke a precocious
maturation of silent synapses in the VC. Likewise, an earlier closure of the CP (> P 27) was
observed in this work for OD-plasticity in PSD-93 KO and VC-restricted PSD-93 KD mice. Since
the sensitive phase for OD-plasticity can be prolonged by rearing animals in the dark (DR) from
birth, this effect was studied on PSD-93 KO mice in this project. PSD-93 KO mice completely
failed to show OD-plasticity after DR, indicating that the faster maturation of PSD- 93 KO mice
is not an experience-dependent process. Recently, it was shown that voluntary physical
exercise can promote OD-plasticity in WT mice. The benefit of running was investigated in
PSD-93 KO mice during the late CP (> P 28). Surprisingly, even physical exercise failed to induce
OD-plasticity, indicating that there is an earlier closure of the CP for OD- plasticity after P
27 in PSD-93 KO mice. Hence, a lack of PSD-93 prevents OD-plasticity which is usually inducible
by DR or voluntary physical exercise in WT mice. Moreover, possible effects of PSD-95 or PSD-
93 KO on visual perception were tested by subjecting mice to a visual discrimination task (VWT).
While visual acuity was normal for both PSD-95 -and PSD-93 KO- mice, orientation
discrimination was severely impaired in both genotypes: KO-mice required more than double
the orientation contrast for a correct behavioral decision compared to WT mice.
In summary, the presented PhD thesis provides evidence that PSD-95 controls the ending ofthe CP for juvenile OD-plasticity, whereas PSD-93 exhibits the opposing function. In contrast
to the current view that increased intracortical inhibition is the major player in closing the CP,
the findings of this PhD study allow the opposing assumption that the closure is mainly based
on PSD-95 function and mostly independent of the inhibitory tone. Taken together, these
results expand the knowledge about the molecular mechanisms underlying synaptic
maturation in VC and enrich the current view concerning the roles of PSD-95 and PSD-93 and
its functional interactions regulating OD-plasticity. | de |
| dc.contributor.coReferee | Gollisch, Tim Prof. Dr. | |
| dc.contributor.thirdReferee | Schlueter, Oliver M. Prof. Dr. Dr. | |
| dc.subject.eng | ocular dominance plasticity | de |
| dc.subject.eng | PSD-95 | de |
| dc.subject.eng | PSD-93 | de |
| dc.subject.eng | optical imaging of intrinsic signals | de |
| dc.subject.eng | MAGUK | de |
| dc.subject.eng | vision | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0023-3F15-A-1 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1005533032
1000147649 | |