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The role of postsynaptic density (PSD) proteins PSD-95 and PSD-93 for mouse visual cortical plasticity and vision

dc.contributor.advisorLoewel, Siegrid Prof. Dr.
dc.contributor.authorStodieck, Sophia Katharina
dc.titleThe role of postsynaptic density (PSD) proteins PSD-95 and PSD-93 for mouse visual cortical plasticity and visionde
dc.contributor.refereeLoewel, Siegrid Prof. Dr.
dc.description.abstractengDuring 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
dc.contributor.coRefereeGollisch, Tim Prof. Dr.
dc.contributor.thirdRefereeSchlueter, Oliver M. Prof. Dr. Dr.
dc.subject.engocular dominance plasticityde
dc.subject.engoptical imaging of intrinsic signalsde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de
dc.identifier.ppn1005533032 1000147649

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