A Study on Potential Sources of Perineuronal Net-Associated Sema3A in Cerebellar Nuclei Reveals Toxicity of Non-Invasive AAV-Mediated Cre Expression in the Central Nervous System

被引：0

作者：

Gimenez, Geoffrey-Alexander ^{[1
,2
]}

Romijn, Maurits ^{[1
]}

van den Herik, Joelle ^{[1
]}

Meijer, Wouter ^{[1
]}

Eggers, Ruben ^{[1
]}

Hobo, Barbara ^{[1
]}

De Zeeuw, Chris I. ^{[2
,3
]}

Canto, Cathrin B. ^{[2
]}

Verhaagen, Joost ^{[1
,4
]}

Carulli, Daniela ^{[1
]}

机构：

[1] Royal Netherlands Acad Arts & Sci, Netherlands Inst Neurosci, Dept Neuroregenerat, Meibergdreef 47, NL-1105 BA Amsterdam, Netherlands

[2] Royal Netherlands Acad Arts & Sci, Netherlands Inst Neurosci, Dept Cerebellar Coordinat & Cognit, Meibergdreef 47, NL-1105 BA Amsterdam, Netherlands

[3] Erasmus MC, Dept Neurosci, NL-3015 GD Rotterdam, Netherlands

[4] Vrije Univ Amsterdam, Amsterdam Neurosci, Ctr Neurogenom & Cognit Res, NL-1081 HZ Amsterdam, Netherlands

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2025年 / 26卷 / 02期

关键词：

Semaphorin; 3A; perineuronal nets; cerebellar nuclei; Purkinje cells; choroid plexus; AAV-PHP.eB; Cre; toxicity; DNA-DAMAGE; ADULT-RAT; IN-VIVO; TRANSGENE EXPRESSION; NEURONAL MARKER; SEMAPHORIN; 3A; PURKINJE; RECOMBINASE; CELLS; MOUSE;

D O I：

10.3390/ijms26020819

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Semaphorin 3A (Sema3A) is an axon guidance molecule, which is also abundant in the adult central nervous system (CNS), particularly in perineuronal nets (PNNs). PNNs are extracellular matrix structures that restrict plasticity. The cellular sources of Sema3A in PNNs are unknown. Most Sema3A-bearing neurons do not express Sema3A mRNA, suggesting that Sema3A may be released from other neurons. Another potential source of Sema3A is the choroid plexus. To identify sources of PNN-associated Sema3A, we focused on the cerebellar nuclei, which contain Sema3A+ PNNs. Cerebellar nuclei neurons receive prominent input from Purkinje cells (PCs), which express high levels of Sema3A mRNA. By using a non-invasive viral vector approach, we overexpressed Cre in PCs, the choroid plexus, or throughout the CNS of Sema3Afl/fl mice. Knocking out Sema3A in PCs or the choroid plexus was not sufficient to decrease the amount of PNN-associated Sema3A. Alternatively, knocking out Sema3A throughout the CNS induced a decrease in PNN-associated Sema3A. However, motor deficits, microgliosis, and neurodegeneration were observed, which were due to Cre toxicity. Our study represents the first attempt to unravel cellular sources of PNN-associated Sema3A and shows that non-invasive viral-mediated Cre expression throughout the CNS could lead to toxicity, complicating the interpretation of Cre-mediated Sema3A knock-out.

引用

页数：21