Publications
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Grødem, Sverre; Thompson, Elise Holter; Røe, Malin Benum; Vatne, Guro Helén; Nymoen, Ingeborg & Buccino, Alessio Paolo
[Show all 10 contributors for this article]
(2025).
Differential impacts of germline and adult aggrecan knockout in PV+ neurons on perineuronal nets and PV+ neuronal function.
Molecular Psychiatry.
ISSN 1359-4184.
30,
p. 2907–2921.
doi:
10.1038/s41380-025-02894-5.
Full text in Research Archive
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Perineuronal nets (PNNs) are a condensed form of extracellular matrix primarily found around parvalbumin-expressing (PV+) interneurons. The postnatal maturation of PV+ neurons is accompanied with the formation of PNNs and reduced plasticity. Alterations in PNN and PV+ neuron function have been described for mental disorders such as schizophrenia and autism. The formation of PNNs is highly dependent on aggrecan, a proteoglycan encoded by the ACAN gene, but it remains unknown if it is produced by the PV+ neurons themselves. Thus, we established a knockout (KO) mouse model (ACANflx/PVcre) and an adeno-associated virus to specifically eliminate aggrecan production from PV+ neurons, in the germline or adult animals, respectively. The germline KO (ACANflx/PVcre) eliminated the expression of PNNs labeled by Wisteria floribunda agglutinin (WFA), the most commonly used PNN marker. Surprisingly, electrophysiological properties of PV+ interneurons and ocular dominance plasticity of adult ACANflx/PVcre mice were similar to controls. In contrast, AAV-mediated ACAN knockout in adult mice increased ocular dominance plasticity. Moreover, in vivo Chondroitinase ABC treatment of KO mice resulted in reduced firing rate of PV+ cells and increased frequency of spontaneous excitatory postsynaptic currents (sEPSC), a phenotype associated with chABC treatment of WT animals. These findings suggest that compensatory mechanisms may be activated during development in response to the germline loss of aggrecan. Indeed, qPCR of bulk tissue indicates that other PNN components, including neurocan and tenascin-R, are expressed at higher levels in the KO animals. Finally, behavioral testing revealed that ACANflx/PVcre mice had similar long-term memory as controls in the Morris water maze. However, they employed bolder search strategies during spatial learning and showed lower level of anxiety-related behavior in an open field and zero maze.
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Grødem, Sverre; Nymoen, Ingeborg; Vatne, Guro Helén; Rogge, Frederik Sebastian; Björnsdottir, Valgerdur & Lensjø, Kristian
[Show all 7 contributors for this article]
(2023).
An updated suite of viral vectors for in vivo calcium imaging using intracerebral and retro-orbital injections in male mice.
Nature Communications.
14(1),
p. 608–1.
doi:
10.1038/s41467-023-36324-3.
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Abstract Genetically encoded Ca 2+ indicators (GECIs) are widely used to measure neural activity. Here, we explore the use of systemically administered PHP.eB AAVs for brain-wide expression of GECIs and compare the expression properties to intracerebrally injected AAVs in male mice. We show that systemic administration is a promising strategy for imaging neural activity. Next, we establish the use of EE-RR- (soma) and RPL10a (Ribo) soma-targeting peptides with the latest jGCaMP and show that EE-RR-tagged jGCaMP8 gives rise to strong expression but limited soma-targeting. In contrast, Ribo-tagged jGCaMP8 lacks neuropil signal, but the expression rate is reduced. To combat this, we modified the linker region of the Ribo-tag (RiboL1-). RiboL1-jGCaMP8 expresses faster than Ribo-jGCaMP8 but remains too dim for reliable use with systemic virus administration. However, intracerebral injections of the RiboL1-tagged jGCaMP8 constructs provide strong Ca 2+ signals devoid of neuropil contamination, with remarkable labeling density.
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Liang, Xiao; Kristiansen, Cecilie Katrin; Mostafavi, Sepideh; Vatne, Guro Helén; Zantingh, Gina Alien & Kianian, Atefeh
[Show all 17 contributors for this article]
(2020).
Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations.
EMBO Molecular Medicine.
ISSN 1757-4676.
12(10),
p. 1–26.
doi:
10.15252/emmm.202012146.
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Mutations in POLG disrupt mtDNA replication and cause devas- tating diseases often with neurological phenotypes. Defining disease mechanisms has been hampered by limited access to human tissues, particularly neurons. Using patient cells carrying POLG mutations, we generated iPSCs and then neural stem cells. These neural precursors manifested a phenotype that faithfully replicated the molecular and biochemical changes found in patient post-mortem brain tissue. We confirmed the same loss of mtDNA and complex I in dopaminergic neurons generated from the same stem cells. POLG-driven mitochondrial dysfunc- tion led to neuronal ROS overproduction and increased cellular senescence. Loss of complex I was associated with disturbed NAD+ metabolism with increased UCP2 expression and reduced phosphorylated SirT1. In cells with compound heterozygous POLG mutations, we also found activated mitophagy via the BNIP3 pathway. Our studies are the first that show it is possible to recapitulate the neuronal molecular and biochemical defects associated with POLG mutation in a human stem cell model. Further, our data provide insight into how mitochondrial dysfunction and mtDNA alterations influence cellular fate deter- mining processes.
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Liang, Xiao; Kristiansen, Cecilie Katrin; Vatne, Guro Helén; Hong, Yu & Bindoff, Laurence
(2020).
Patient-specific neural progenitor cells derived from induced pluripotent stem cells offer a promise of good models for mitochondrial disease.
Cell and Tissue Research.
ISSN 0302-766X.
380(1),
p. 15–30.
doi:
10.1007/s00441-019-03164-x.
Full text in Research Archive
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Raasakka, Arne; Ruskamo, Salla; Barker, Robert; Krokengen, Oda Caspara; Vatne, Guro Helén & Kristiansen, Cecilie Katrin
[Show all 13 contributors for this article]
(2019).
Neuropathy-related mutations alter the membrane binding properties of the human myelin protein P0 cytoplasmic tail.
PLOS ONE.
14:e0216833(6),
p. 1–24.
doi:
10.1371/journal.pone.0216833.
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Schwann cells myelinate selected axons in the peripheral nervous system (PNS) and contribute to fast saltatory conduction via the formation of compact myelin, in which water is excluded from between tightly adhered lipid bilayers. Peripheral neuropathies, such as Charcot-Marie-Tooth disease (CMT) and Dejerine-Sottas syndrome (DSS), are incurable demyelinating conditions that result in pain, decrease in muscle mass, and functional impairment. Many Schwann cell proteins, which are directly involved in the stability of compact myelin or its development, are subject to mutations linked to these neuropathies. The most abundant PNS myelin protein is protein zero (P0); point mutations in this transmembrane protein cause CMT subtype 1B and DSS. P0 tethers apposing lipid bilayers together through its extracellular immunoglobulin-like domain. Additionally, P0 contains a cytoplasmic tail (P0ct), which is membrane-associated and contributes to the physical properties of the lipid membrane. Six CMT- and DSS-associated missense mutations have been reported in P0ct. We generated recombinant disease mutant variants of P0ct and characterized them using biophysical methods. Compared to wild-type P0ct, some mutants have negligible differences in function and folding, while others highlight functionally important amino acids within P0ct. For example, the D224Y variant of P0ct induced tight membrane multilayer stacking. Our results show a putative molecular basis for the hypermyelinating phenotype observed in patients with this particular mutation and provide overall information on the effects of disease-linked mutations in a flexible, membrane-binding protein segment. Using neutron reflectometry, we additionally show that P0ct embeds deep into a lipid bilayer, explaining the observed effects of P0ct on the physical properties of the membrane.
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Ruskamo, Salla; Nieminen, Tuomo; Kristiansen, Cecilie Katrin; Vatne, Guro Helén; Baumann, Anne & Hallin, Erik Ingmar
[Show all 11 contributors for this article]
(2017).
Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2.
Scientific Reports.
7:6510,
p. 1–13.
doi:
10.1038/s41598-017-06781-0.
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Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies. Recently, three CMT1-associated point mutations (I43N, T51P, and I52T) were discovered in the abundant peripheral myelin protein P2. These mutations trigger abnormal myelin structure, leading to reduced nerve conduction velocity, muscle weakness, and distal limb atrophy. P2 is a myelin-specific protein expressed by Schwann cells that binds to fatty acids and membranes, contributing to peripheral myelin lipid homeostasis. We studied the molecular basis of the P2 patient mutations. None of the CMT1-associated mutations alter the overall folding of P2 in the crystal state. P2 disease variants show increased aggregation tendency and remarkably reduced stability, T51P being most severe. In addition, P2 disease mutations affect protein dynamics. Both fatty acid binding by P2 and the kinetics of its membrane interactions are affected by the mutations. Experiments and simulations suggest opening of the β barrel in T51P, possibly representing a general mechanism in fatty acid-binding proteins. Our findings demonstrate that altered biophysical properties and functional dynamics of P2 may cause myelin defects in CMT1 patients. At the molecular level, a few malformed hydrogen bonds lead to structural instability and misregulation of conformational changes related to ligand exchange and membrane binding.
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Published
Oct. 7, 2020 5:54 PM
- Last modified
Oct. 7, 2020 5:54 PM