Contributions
Abstract: 216
Type: Scientific Session
Abstract Category: Pathology and pathogenesis of MS - Neurodegeneration
Introduction: Grey matter alterations are increasingly recognized in multiple sclerosis (MS) and contribute to disability and prevalent impairment of higher cognitive functions. However, the impact of inflammatory processes on grey matter structure and function remains poorly understood.
Objectives: To assess the local effects of neuroinflammation on cortical circuits and single pyramidal neurons in an animal model of cortical MS.
Methods: After establishing a mouse model of cortical multiple sclerosis we used chronic and acute two-photon calcium imaging in anesthetized animals to assess neuronal activity in inflammatory lesions of the neocortex and baseline calcium concentrations in single dendrites and synaptic spines. In a combination of light and electron microscopy we studied synaptic loss in individual cortical projection neurons by reconstructing their dendritic arbours and assessed phagocyte populations and their role in synaptic removal.
Results: Chronic two-photon imaging of neuronal activity showed a drop of neuronal firing in cortical projection neurons, which started within three days of onset of cortical neuroinflammation. We observed a sharp and acute reduction in synapse numbers on the dendritic arbours of pyramidal neurons throughout the cortical layers. Subcellular imaging of calcium concentrations in neurites revealed local calcium overload in individual spines which tagged them for subsequent removal. The density of synapse and local network activity recovered within a week, while other structural alterations, such as demyelination persisted for much longer. These acute changes coincided with activation of resident microglia and infiltration of blood-derived macrophages that showed increased uptake of synaptic material. Pharmacological interference with phagocyte activation lead to a significant protection from spine loss.
Summary: Our study of cortical neuroinflammation reveals the structural and functional dynamics of cortical pathology and subsequent compensation, provides a cellular and subcellular mechanistic framework for synaptic loss in inflammatory lesions and demonstrates a potential treatment strategy with possibilities for translation into MS patients.
Disclosure: Conflict of interest: This research project has been supported as part of a collaboration between LMU and Sanofi. NH, LW, DO are employees of Sanofi. No other conflict of interest relevant for this project is being reported by the authors.
AM Schumacher: nothing to disclose
M Jafari: nothing to disclose
N Snaidero: nothing to disclose
T Neziraj: nothing to disclose
SS Smith: nothing to disclose
J Flores-Weidinger: nothing to disclose
N Hagan: Employee of Sanofi
L Woodsworth: Employee of Sanofi
D Ofengeim: Employee of Sanofi
T Jürgens: nothing to disclose
D Merkler: nothing to disclose
T Misgeld: nothing to disclose
M. Kerschensteiner: In the past, M. Kerschensteiner has received honoraria for consulting and presentations from AbbVie, Almirall, Biogen, Med-
Day, Novartis, Roche, Sanofi, as well as research support
from Biogen and Sanofi.
Abstract: 216
Type: Scientific Session
Abstract Category: Pathology and pathogenesis of MS - Neurodegeneration
Introduction: Grey matter alterations are increasingly recognized in multiple sclerosis (MS) and contribute to disability and prevalent impairment of higher cognitive functions. However, the impact of inflammatory processes on grey matter structure and function remains poorly understood.
Objectives: To assess the local effects of neuroinflammation on cortical circuits and single pyramidal neurons in an animal model of cortical MS.
Methods: After establishing a mouse model of cortical multiple sclerosis we used chronic and acute two-photon calcium imaging in anesthetized animals to assess neuronal activity in inflammatory lesions of the neocortex and baseline calcium concentrations in single dendrites and synaptic spines. In a combination of light and electron microscopy we studied synaptic loss in individual cortical projection neurons by reconstructing their dendritic arbours and assessed phagocyte populations and their role in synaptic removal.
Results: Chronic two-photon imaging of neuronal activity showed a drop of neuronal firing in cortical projection neurons, which started within three days of onset of cortical neuroinflammation. We observed a sharp and acute reduction in synapse numbers on the dendritic arbours of pyramidal neurons throughout the cortical layers. Subcellular imaging of calcium concentrations in neurites revealed local calcium overload in individual spines which tagged them for subsequent removal. The density of synapse and local network activity recovered within a week, while other structural alterations, such as demyelination persisted for much longer. These acute changes coincided with activation of resident microglia and infiltration of blood-derived macrophages that showed increased uptake of synaptic material. Pharmacological interference with phagocyte activation lead to a significant protection from spine loss.
Summary: Our study of cortical neuroinflammation reveals the structural and functional dynamics of cortical pathology and subsequent compensation, provides a cellular and subcellular mechanistic framework for synaptic loss in inflammatory lesions and demonstrates a potential treatment strategy with possibilities for translation into MS patients.
Disclosure: Conflict of interest: This research project has been supported as part of a collaboration between LMU and Sanofi. NH, LW, DO are employees of Sanofi. No other conflict of interest relevant for this project is being reported by the authors.
AM Schumacher: nothing to disclose
M Jafari: nothing to disclose
N Snaidero: nothing to disclose
T Neziraj: nothing to disclose
SS Smith: nothing to disclose
J Flores-Weidinger: nothing to disclose
N Hagan: Employee of Sanofi
L Woodsworth: Employee of Sanofi
D Ofengeim: Employee of Sanofi
T Jürgens: nothing to disclose
D Merkler: nothing to disclose
T Misgeld: nothing to disclose
M. Kerschensteiner: In the past, M. Kerschensteiner has received honoraria for consulting and presentations from AbbVie, Almirall, Biogen, Med-
Day, Novartis, Roche, Sanofi, as well as research support
from Biogen and Sanofi.