Neurologic and Psychiatric Disorders: from synapses to networks

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Organizational Unit

Publications

Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ

Publication . Marttinen, Mikael; Ferreira, Catarina B.; Paldanius, Kaisa M. A.; Takalo, Mari; Natunen, Teemu; Mäkinen, Petra; Leppänen, Luukas; Leinonen, Ville; Tanigaki, Kenji; Kang, Gina; Hiroi, Noboru; Soininen, Hilkka; Rilla, Kirsi; Haapasalo, Annakaisa; Hiltunen, Mikko

Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells.

2020Journal article

Open access

Role of adenosine in epilepsy and seizures

Publication . Tescarollo, Fabio C.; Rombo, Diogo M.; DeLiberto, Lindsay K.; Fedele, Denise E.; Alharfoush, Enmar; Tomé, Ângelo R.; Cunha, Rodrigo A.; Sebastião, Ana M; Boison, Detlev

Adenosine is an endogenous anticonvulsant and neuroprotectant of the brain. Seizure activity produces large quantities of adenosine, and it is this seizure-induced adenosine surge that normally stops a seizure. However, within the context of epilepsy, adenosine plays a wide spectrum of different roles. It not only controls seizures (ictogenesis), but also plays a major role in processes that turn a normal brain into an epileptic brain (epileptogenesis). It is involved in the control of abnormal synaptic plasticity and neurodegeneration and plays a major role in the expression of comorbid symptoms and complications of epilepsy, such as sudden unexpected death in epilepsy (SUDEP). Given the important role of adenosine in epilepsy, therapeutic strategies are in development with the goal to utilize adenosine augmentation not only for the suppression of seizures but also for disease modification and epilepsy prevention, as well as strategies to block adenosine A2A receptor overfunction associated with neurodegeneration. This review provides a comprehensive overview of the role of adenosine in epilepsy.

2020Journal article

Restricted access

Pupil dilation reflects the authenticity of received nonverbal vocalizations

Publication . Cosme, Gonçalo; Rosa, Pedro J.; Lima, César F.; Tavares, Vânia; Scott, Sophie; Chen, Sinead; Wilcockson, Thomas D. W.; Crawford, Trevor J.; Prata, Diana

The ability to infer the authenticity of other’s emotional expressions is a social cognitive process taking place in all human interactions. Although the neurocognitive correlates of authenticity recognition have been probed, its potential recruitment of the peripheral autonomic nervous system is not known. In this work, we asked participants to rate the authenticity of authentic and acted laughs and cries, while simultaneously recording their pupil size, taken as proxy of cognitive effort and arousal. We report, for the first time, that acted laughs elicited higher pupil dilation than authentic ones and, reversely, authentic cries elicited higher pupil dilation than acted ones. We tentatively suggest the lack of authenticity in others’ laughs elicits increased pupil dilation through demanding higher cognitive effort; and that, reversely, authenticity in cries increases pupil dilation, through eliciting higher emotional arousal. We also show authentic vocalizations and laughs (i.e. main effects of authenticity and emotion) to be perceived as more authentic, arousing and contagious than acted vocalizations and cries, respectively. In conclusion, we show new evidence that the recognition of emotional authenticity can be manifested at the level of the autonomic nervous system in humans. Notwithstanding, given its novelty, further independent research is warranted to ascertain its psychological meaning.

2021Journal article

Open access

Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity

Publication . Mouro, Francisco; Ribeiro, Joaquim A.; Sebastião, Ana M; Dawson, Neil

Elucidating how cannabinoids affect brain function is instrumental for the development of therapeutic tools aiming to mitigate 'on target' side effects of cannabinoid-based therapies. A single treatment with the cannabinoid receptor agonist, WIN 55,212-2, disrupts recognition memory in mice. Here, we evaluate how prolonged, intermittent (30 days) exposure to WIN 55,212-2 (1 mg/kg) alters recognition memory and impacts on brain metabolism and functional connectivity. We show that chronic, intermittent treatment with WIN 55,212-2 disrupts recognition memory (Novel Object Recognition Test) without affecting locomotion and anxiety-like behaviour (Open Field and Elevated Plus Maze). Through 14 C-2-deoxyglucose functional brain imaging we show that chronic, intermittent WIN 55,212-2 exposure induces hypometabolism in the hippocampal dorsal subiculum and in the mediodorsal nucleus of the thalamus, two brain regions directly involved in recognition memory. In addition, WIN 55,212-2 exposure induces hypometabolism in the habenula with a contrasting hypermetabolism in the globus pallidus. Through the application of the Partial Least Squares Regression (PLSR) algorithm to the brain imaging data, we observed that prolonged WIN 55,212-2 administration alters functional connectivity in brain networks that underlie recognition memory, including that between the hippocampus and prefrontal cortex, the thalamus and prefrontal cortex, and between the hippocampus and the perirhinal cortex. In addition, our results support disturbed lateral habenula and serotonin system functional connectivity following WIN 55,212-2 exposure. Overall, this study provides new insight into the functional mechanisms underlying the impact of chronic cannabinoid exposure on memory and highlights the serotonin system as a particularly vulnerable target.

2018Journal article

Open access

Amyotrophic Lateral Sclerosis ALS and adenosine receptors

Publication . Sebastião, Ana M; Rei, Nádia; Ribeiro, Joaquim A.

In the present review we discuss the potential involvement of adenosinergic signaling, in particular the role of adenosine receptors, in amyotrophic lateral sclerosis (ALS). Though the literature on this topic is not abundant, the information so far available on adenosine receptors in animal models of ALS highlights the interest to continue to explore the role of these receptors in this neurodegenerative disease. Indeed, all motor neurons affected in ALS are responsive to adenosine receptor ligands but interestingly, there are alterations in pre-symptomatic or early symptomatic stages that mirror those in advanced disease stages. Information starts to emerge pointing toward a beneficial role of A2A receptors (A2AR), most probably at early disease states, and a detrimental role of caffeine, in clear contrast with what occurs in other neurodegenerative diseases. However, some evidence also exists on a beneficial action of A2AR antagonists. It may happen that there are time windows where A2AR prove beneficial and others where their blockade is required. Furthermore, the same changes may not occur simultaneously at the different synapses. In line with this, it is not fully understood if ALS is a dying back disease or if it propagates in a centrifugal way. It thus seems crucial to understand how motor neuron dysfunction occurs, how adenosine receptors are involved in those dysfunctions and whether the early changes in purinergic signaling are compensatory or triggers for the disease. Getting this information is crucial before starting the design of purinergic based strategies to halt or delay disease progression.

2018Journal article

Open access