Andrea Mancini

Erratum: Persistent activation of microglia and NADPH oxidase drive hippocampal dysfunction in experimental multiple sclerosis.

Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression.

Synaptic plasticity and experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

Structural and functional neuronal plasticity could play a crucial role during the course of multiple sclerosis (MS). The immune system and the central nervous system (CNS) strictly interact in physiologic conditions and during inflammation to modulate neuroplasticity and in particular the ability of the synapses to undergo long-term changes in the efficacy of synaptic transmission, such as long-term potentiation (LTP). During MS, neuro-inflammation might deeply influence the ability of neuronal networks to express physiologic plasticity, reducing the plastic reserve of the brain, with a negative impact on symptoms progression and cognitive performances. In this manuscript we review the evidence on synaptic plasticity alterations in experimental autoimmune encephalomyelitis (EAE), the most diffuse and widely utilized experimental model of MS, together with their potential underlying mechanisms and clinical relevance. This article is part of a Special Issue entitled SI: Brain and Memory.

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

Cognitive impairment is very frequent during multiple sclerosis (MS), involving approximately 40–70% of the patients, with a profound impact on patient’s life. It is now established that among the various central nervous system (CNS) structures involved during the course of MS, the hippocampus is particularly sensitive to the detrimental effects of neuroinflammation. Different studies demonstrated hippocampal involvement during MS, in association with depression and cognitive impairment, such as verbal and visuo-spatial memory deficits, even during the earlier phases of the disease. These cognitive alterations could represent the visible consequences of a hidden synaptic impairment. Indeed, neuronal and immune functions are intertwined and the immune system is able to modulate the efficacy of synaptic transmission and the induction of the main forms of synaptic plasticity, such as long term potentiation (LTP). Hippocampal synaptic plasticity has been studied during the last decades as the physiological basis of human learning and memory and its disruption can be associated with behavioral and cognitive abnormalities. The aim of the present work is to review the available evidence about the presence of hippocampal synaptic plasticity alterations in experimental models of MS, specifically during the course of experimental autoimmune encephalomyelitis (EAE) and to discuss their relevance with regard to human MS. Indeed, the failure of synapses to express plasticity during neuroinflammation could potentially lead to a progressive failure of the brain plastic reserve, possibly contributing to disability progression and cognitive impairment during MS.

Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain dopamine (DA) neurons. Mutation of leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this kinase has to be fully understood yet. Hyperactivation of Lrrk2 kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD. To investigate possible alterations of striatal susceptibility to mitochondrial dysfunction, we performed electrophysiological recordings from the nucleus striatum of a G2019S Lrrk2 mouse model of PD, as well as molecular and morphological analyses of G2019S Lrrk2-expressing SH-SY5Y neuroblastoma cells. In G2019S mice, we found reduced striatal DA levels, according to the hypothesis of alteration of dopaminergic transmission, and increased loss of field potential induced by the mitochondrial complex I inhibitor rotenone. This detrimental effect is reversed by the D2 DA receptor agonist quinpirole via the inhibition of the cAMP/PKA intracellular pathway. Analysis of mitochondrial functions in G2019S Lrrk2-expressing SH-SY5Y cells revealed strong rotenone-induced oxidative stress characterized by reduced Ca2+ buffering capability and ATP synthesis, production of reactive oxygen species, and increased mitochondrial fragmentation. Importantly, quinpirole was able to prevent all these changes. We suggest that the G2019S-Lrrk2 mutation is a predisposing factor for enhanced striatal susceptibility to mitochondrial dysfunction induced by exposure to mitochondrial environmental toxins and that the D2 receptor stimulation is neuroprotective on mitochondrial function, via the inhibition of cAMP/PKA intracellular pathway. We suggest new possible neuroprotective strategies for patients carrying this genetic alteration based on drugs specifically targeting Lrrk2 kinase domain and mitochondrial functionality.

Erratum: Erratum: Persistent activation of microglia and NADPH oxidase drive hippocampal dysfunction in experimental multiple sclerosis

The original version of this Article contained an error in the title of the paper, where “Persistent activation of microglia and NADPH oxidase drive hippocampal dysfunction in experimental multiple sclerosis” was incorrectly given as “Persistent activation of microglia and NADPH drive hippocampal dysfunction in experimental multiple sclerosis”. This has now been corrected in the PDF and HTML versions of the Article.

Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets.

Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease

Among genetic abnormalities identified in Parkinsons disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice. In G2019S Lrrk2 KI mice, basal spontaneous glutamatergic transmission, synaptic facilitation, and NMDA/AMPA ratios were unchanged, whereas the stimulation of dopamine (DA) D2 receptor by quinpirole reduced the spontaneous and evoked excitatory postsynaptic currents (EPSC). Quinpirole reduced the EPSC amplitude of SPNs in KI but not in KD, KO and WT mice, suggesting that the enhanced LRRK2 kinase activity induced by the G2019S mutation is associated with the observed functional alteration of SPNs synaptic transmission. The effect of quinpirole was mediated by a phospholipase C (PLC)-dependent release of endocannabinoid, with subsequent activation of presynaptic cannabinoid receptor 1 and reduced release of glutamate. The key role of DA D2 receptor in reducing glutamatergic output in our LRRK2 genetic model of PD further supports the use of DA agonists in the treatment of early PD patients with LRRK2 mutations to counteract the disease progression.

Multiple sclerosis and cognition: synaptic failure and network dysfunction

Cognitive impairment is increasingly recognized to be a core feature of multiple sclerosis (MS), with important implications for the everyday life of individuals with MS and for disease management. Unfortunately, the exact mechanisms that underlie this cognitive impairment are poorly understood and there are no effective therapeutic options for this aspect of the disease. During MS, focal brain inflammatory lesions, together with pathological changes of both CNS grey matter and normal-appearing white matter, can interfere with cognitive functions. Moreover, inflammation may alter the crosstalk between the immune and the nervous systems, modulating the induction of synaptic plasticity and neurotransmission. In this Review, we examine the CNS structures and cognitive domains that are affected by the disease, with a specific focus on hippocampal involvement in MS and experimental autoimmune encephalomyelitis, an experimental model of MS. We also discuss the hypothesis that, during MS, immune-mediated alterations of synapses’ ability to express long-term plastic changes may contribute to the pathogenesis of cognitive impairment by interfering with the dynamics of neuronal networks.Cognitive impairment is a key feature of multiple sclerosis (MS). Di Filippo and colleagues provide an overview of the cognitive domains and brain regions that are affected in MS, with a focus on potential hippocampal mechanisms underlying learning and memory deficits in this disease.

Visual pathway involvement in multiple sclerosis: Look straight in the eyes

Visual symptoms are a common clinical manifestation of multiple sclerosis (MS) and are frequently due to acute optic neuritis (ON). However, the entire visual pathway can be involved throughout the disease course. We describe the case of a young MS patient who experienced visual symptoms that were eventually found to be caused by retinal periphlebitis, an inflammatory process of the anterior visual pathway, which is common during MS, but rarely symptomatic. This case reinforces the concept that in all MS patients complaining visual symptoms, a complete work-up should be performed in order to rule out possible ON mimicries.