| 1. |
- Guyon, Nicolas, et al.
(författare)
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Adult trkB signaling in parvalbumin interneurons is essential to prefrontal network dynamics
- 2021
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Ingår i: Journal of Neuroscience. - Stockholm : Karolinska Institutet, Dept of Neuroscience. - 0270-6474. ; 41:14, s. 3120-3141
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of c oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.
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| 2. |
- Johard, Helena, et al.
(författare)
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HCN Channel Activity Balances Quiescence and Proliferation in Neural Stem Cells and Is a Selective Target for Neuroprotection During Cancer Treatment
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:10, s. 1522-1533
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Tidskriftsartikel (refereegranskat)abstract
- Children suffering from neurologic cancers undergoing chemotherapy and radiotherapy are at high risk of reduced neurocognitive abilities likely via damage to proliferating neural stem cells (NSC). Therefore, strategies to protect NSCs are needed. We argue that induced cell-cycle arrest/quiescence in NSCs during cancer treatment can represent such a strategy. Here, we show that hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are dynamically expressed over the cell cycle in NSCs, depolarize the membrane potential, underlie spontaneous calcium oscillations and are required to maintain NSCs in the actively proliferating pool. Hyperpolarizing pharmacologic inhibition of HCN channels during exposure to ionizing radiation protects NSCs cells in neurogenic brain regions of young mice. In contrast, brain tumor-initiating cells, which also express HCN channels, remain proliferative during HCN inhibition.
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| 3. |
- Mulder, Jan, et al.
(författare)
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Secretagogin is a Ca2+-binding protein specifying subpopulations of telencephalic neurons
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:52, s. 22492-22497
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Tidskriftsartikel (refereegranskat)abstract
- The Ca2+-binding proteins (CBPs) parvalbumin, calbindin, and calretinin are phenotypic markers of terminally differentiated neurons in the adult brain. Although subtle phylogenetic variations in the neuronal distribution of these CBPs may occur, morphologically and functionally diverse subclasses of interneurons harbor these proteins in olfactory and corticolimbic areas. Secretagogin (scgn) is a recently cloned CBP from pancreatic beta and neuroendocrine cells. We hypothesized that scgn is expressed in the mammalian brain. We find that scgn is a marker of neuroblasts commuting in the rostral migratory stream. Terminally differentiated neurons in the olfactory bulb retain scgn expression, with scgn being present in periglomerular cells and granular layer interneurons. In the corticolimbic system, scgn identifies granule cells distributed along the dentate gyrus, indusium griseum, and anterior hippocampal continuation emphasizing the shared developmental origins, and cytoarchitectural and functional similarities of these neurons. We also uncover unexpected phylogenetic differences in scgn expression, since this CBP is restricted to primate cholinergic basal forebrain neurons. Overall, we characterize scgn as a neuron-specific CBP whose distribution identifies neuronal subtypes and hierarchical organizing principles in the mammalian brain.
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| 4. |
- Zilberter, Misha
(författare)
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Synaptic plasticity in local networks of neocortical layer 2/3
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The neocortex is a hierarchal organ in which information processing takes on place on many levels, from subcellular signalling all the way to neural networks. Neocortical local neuronal networks (microcircuits), composed of interconnected neurons, form elementary information processing units within the cortex. Pyramidal cells, the primary glutamatergic cells in the cortex, receive synaptic input both from within the neocortex and from more distant cortical and sub-cortical regions. The strength of these inputs can be modified on various time scales. The strength of pyramidal-pyramidal (P-P) cell unitary connections can be modified long-term, depending on the timing of action potentials (APs) in the pre- and post-synaptic cells (spike-timing dependent plasticity, STDP). We reported that the learning rule governing STDP modification is regulated by preceding activity in a postsynaptic neuron. Moreover, we have shown that the difference between STDP observed at layer 2/3 (L2/3) P-P cell connections and STDP studied at other excitatory connections in the neocortex is attributed to a fundamental difference in synaptic properties, suggesting that a L2/3 pyramidal cell is able to recognize its presynaptic partner and form physiologically distinct synapses based on the origin of input. Additionally, the time-window for the induction phase of spike timing- dependent long-term potentiation (STD-LTP) and depression (LTD) at L2/3 P-P connections and its dependence on post-synaptic cell spine calcium concentrations was further examined using data-based computational modelling. We have shown that the resulting synaptic gain change depends on a 15 ms window following synaptic activation. Our data suggested a theoretical enzyme-like Ca2+ sensor that could account for the observed synaptic gain changes in L2/3 P-P connections. Synaptic LTP is thought to be a crucial component underlying learning and memory. Neurodegenerative disorders, such as the Alzheimer s disease (AD) are commonly associated with cognitive impairment and memory loss. We reported that STD-LTP induction at excitatory inputs onto L2/3 pyramidal cells in a mouse model of Alzheimer s disease was impaired as early as at 3.5 months of age, at the very onset of AD-like pathology and prior to amyloid plaque formation. STD-LTP was also abolished at L2/3 P-P connections in wild-type brain slices after soluble non-fibrillar Abeta(25-35) application. The underlying mechanism was the selective Abeta-induced reduction of AMPAR-mediated currents. Meanwhile, STD-LTP induction could be rescued by application of AMPAR desensitization antagonist, cyclothiazide. Thus, we have demonstrated a novel target for AD pathology as well as a means of rescuing STDP under AD s neurodegenerative conditions. Synaptic plasticity consists of multiple variations in synaptic gain taking place over different time scales and between different cell types. In another instance, inhibitory connections from FSN interneuron onto the pyramidal cell can undergo short-term changes in synaptic gain following a postsynaptic AP burst. Previous studies suggested that retrograde dendritic release of glutamate regulates such short-term changes. We further clarified the molecular mechanism of retrograde signalling by showing the SAT2-mediated glutamine transport to be is a necessary precursor for retrograde signalling at FSN-pyramidal cell connections, substantiating the role of glutamate as a retrograde messenger at this synapse.
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