CaV2.2 Channels in Brain Development and Synaptic Plasticity

In the mammalian brain, presynaptic CaV2.2 channels play a pivotal role for synaptic transmission by mediating fast neurotransmitter exocytosis via influx of Ca2+ into the active zone at the presynaptic terminal. The distribution and activity of CaV2.2 channels at different synapses and maturity stages in the brain remains to be elucidated. In this study, I first show high levels of CaV2.2 channels in mouse cortex and hippocampus throughout development, persisting into adulthood. In contrast, CaV2.2 channels in the cerebellum and brain stem decreased as the brain matured. I thereafter assessed CaV2.2 channels during homeostatic synaptic plasticity, a compensatory form of homeostatic control preventing excessive or insufficient neuronal activity during which extensive active zone remodelling has been described. In this work I show that chronic silencing of neuronal activity in mature hippocampal cultures resulted in elevated presynaptic Ca2+ transients, mediated by a 30 % increase in CaV2.2 channel levels at the presynapse. Next, this work focussed on α2δ-1 subunits, important regulators of synaptic transmission and CaV2.2 channel abundance at the presynaptic membrane. Here, I show that α2δ-1- overexpression reduces the contribution of CaV2.2 channels to total Ca2+ flux without altering the amplitude of the Ca2+ transients. Finally, levels of endogenous α2δ-1 decreased during homeostatic synaptic plasticity, whereas the overexpression of α2δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for CaV2.2 channels and novel roles for α2δ-1 during plastic synaptic adaptation

Involvement of CaV2.2 channels and α2δ-1 in homeostatic synaptic plasticity in cultured hippocampal neurons

In the mammalian brain, presynaptic CaV2 channels play a pivotal role for synaptic transmission by mediating fast neurotransmitter exocytosis via influx of Ca2+ into the active zone of presynaptic terminals. However, the distribution and modulation of CaV2.2 channels at plastic hippocampal synapses remains to be elucidated. Here, we assess CaV2.2 channels during homeostatic synaptic plasticity, a compensatory form of homeostatic control preventing excessive or insufficient neuronal activity during which extensive active zone remodelling has been described. We show that chronic silencing of neuronal activity in mature hippocampal cultures resulted in elevated presynaptic Ca2+ transients, mediated by increased levels of CaV2.2 channels at the presynaptic site. This work focussed further on the role of α2δ-1 subunits, important regulators of synaptic transmission and CaV2.2 channel abundance at the presynaptic membrane. We find that α2δ-1-overexpression reduces the contribution of CaV2.2 channels to total Ca2+ flux without altering the amplitude of the Ca2+ transients. Levels of endogenous α2δ-1 decreased during homeostatic synaptic plasticity, whereas the overexpression of α2δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for CaV2.2 channels and novel roles for α2δ-1 during synaptic plastic adaptation

MR Elastography-Based Assessment of Matrix Remodeling at Lesion Sites Associated With Clinical Severity in a Model of Multiple Sclerosis

Magnetic resonance imaging (MRI) with gadolinium based contrast agents (GBCA) is routinely used in the clinic to visualize lesions in multiple sclerosis (MS). Although GBCA reveal endothelial permeability, they fail to expose other aspects of lesion formation such as the magnitude of inflammation or tissue changes occurring at sites of blood-brain barrier (BBB) disruption. Moreover, evidence pointing to potential side effects of GBCA has been increasing. Thus, there is an urgent need to develop GBCA-independent imaging tools to monitor pathology in MS. Using MR-elastography (MRE), we previously demonstrated in both MS and the animal model experimental autoimmune encephalomyelitis (EAE) that inflammation was associated with a reduction of brain stiffness. Now, using the relapsing-remitting EAE model, we show that the cerebellum-a region with predominant inflammation in this model-is especially prone to loss of stiffness. We also demonstrate that, contrary to GBCA-MRI, reduction of brain stiffness correlates with clinical disability and is associated with enhanced expression of the extracellular matrix protein fibronectin (FN). Further, we show that FN is largely expressed by activated astrocytes at acute lesions, and reflects the magnitude of tissue remodeling at sites of BBB breakdown. Therefore, MRE could emerge as a safe tool suitable to monitor disease activity in MS

Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy

Voltage-gated calcium (CaV) channels form three sub-families (CaV1-3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1-4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy (DEE). Patient 1 has a homozygous frameshift variant c.818_821dup/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of α2δ-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c.13_23dup/p.(Leu9Alafs*5), highly likely representing a null allele, and a missense variant c.626G>A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit, with strongly reduced trafficking of α2δ-1G209D to the cell surface, and a complete inability of α2δ-1G209D to increase the trafficking and function of CaV2 channels. Thus biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of α2δ-1 and other α2δ proteins for normal human neuronal development

Therapeutic complement inhibition: a promising approach for treatment of neuroimmunological diseases.

INTRODUCTION Autoimmunity is an important cause of disease both in the central and peripheral nervous systems. Aetiologies and clinical manifestations are complex and heterogeneous. Inappropriate control of complement activation at inappropriate sites has been recognized as a major determinant in several neurological conditions, including Guillain-Barré syndrome and neuromyelitis optica. In each case pathogenesis is thought to be associated with generation of autoantibodies which upon binding guide activation of the complement system to self-tissue. Areas covered: Modulation of the complement system activation at such sites may represent a novel therapeutic approach for treatment of immune-mediated inflammatory conditions. In this review we focus on the therapeutic effects of complement inhibitors in Guillain-Barré syndrome and neuromyelitis optica and highlight recent developments within the field. Expert Commentary: Conventional first line treatment strategies in GBS and NMO have the potential disadvantage of causing widespread immunosuppressive effects. A more targeted approach may therefore be more effective and less disruptive to the immune system, especially in the case of NMO, which requires long term immunosuppression. Modulation of the complement system may hold the key and has already been shown to be of clinical benefit in other non-neurological conditions, including paroxysmal nocturnal hemoglobinuria and hereditary angioedema

Increased surface P2X4 receptor regulates anxiety and memory in P2X4 internalization-defective knock-in mice

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