Benjamin Portal

Post doc. vid Institutionen för medicinsk cellbiologi, Forskargrupp Mia Lindskog

Husargatan 3
751 23 Uppsala
Box 571
751 23 UPPSALA

Kort presentation

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Graduated from the University of Paris-Salcay and University of Toulouse, my expertise covers basic neuroscience and neuropharmacology.. I am mainly interrested in the the biological processes of brain disorders such as depression/anxiety or Alzheimer's disease.

Whilst my PhD work was focused on the role of astroglial connexins in the response to antidepressant, my current project investigates early neuronal and astroglial impairments in Alzheimer's disease.

Nyckelord: pharmacology alzheimers disease electrophysiology behavior

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My main research is centred on the importance of glial cells, and mostly astorcytes, in brain disorders.

Thanks to a three-year grant obtained from the French Government, I focused my PhD work at the Research Center on Animal Cognition (Toulouse, France) on the role astroglial hemichannels in the mode of action of antidepressant drugs (mostly Selective Serotonin Re-uptake Inhibitors - SSRI). Combining behavioral observations, microdialysis and conventional molecular biology tools, we successfully charactherized the importance of these protein in physiological and pathological condition, as well as in the mode of action of Fluoxetine (Prozac®), a broad used SSRI in the treatment of depression.

After my dissertation in 2019, I joined Maria Lindskog's lab as a post-doc fellow. Thanks to the Wenner-Gren fellowship for foreign researchers, I started a brand new project studying early neuronal and astroglial impairments in Alzheimer's disease. Notably through local collaboration with Anna Erlandsson (Uppsala University), Per Nilsson and Maria Ankarcrona (Karolinska Institute) and Hjalmar Brissmar (SciLife labs in Stockholm), we recently unveiled neuronal dysfunctions in an APP knock-in model of Alzheimer's disease, long before the apparition of the characteristic amyloid-β plaques.

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Discovered in 1906, Alzheimer's disease is now well documented, notably thanks to post-mortem observations. Many molecular changes have been unveiled in that neurodenerative disease, which is mostly characterised by an important memory loss. Among others, Tau neurofibrillary tangles and Amiloïd-beta (Aβ) are the main identified markers for the pathology. About 25% of all Alzheimer's disease forms are genetic and unfortunately, there are to date no disease modifying treatment. Hence the ongoing research aims at identifying new read-outs, interesting for the treatment of the pathology.

The late phases of Alzheimer's disease are very well described. In that context, Tau neurofibrillary tangles and Aβ depositions are believed to be the cause of neuronal impairements, thus observed dementia. However, a recent study revealed early functional changes in fast-spiking GABA-ergic neurons in the hippocampus of young transgenic mice, model of familiar forms of Alzheimer's disease (Arroyo-Garcia LE et al., 2021).. Following these findings, we recently observed hyper sensitive glutamatergic neurons in area CA1 of the hippocampus of 6-month old animal model of Alzheimer's disease. Our research project is therefore articulated around three main axis:

1. Understand the behavioral consequences of early neuronal impairments

In patients, the lack of social interaction at early stages of the disease is a strong contributing factor to the later-on symptoms (Friedler B et al., 2015), such as high anxiety, depression and perhaps memory loss. In APPNL-F mice (Saito T et al., 2014), we therefore hypothesize that six-months old animals (who don't have amyloid depositions) would show a lack of social memory and to a larger extent a reduced of social interaction. Social memory will be assess with a five trials social assay. We also. AD presents a high comorbidity with depression (for review (Teri L and Wagner A, 1992)). Interestingly, a recent study reported depressive-like and anxiety-like behavior before plaque formation in an APP knock-in mouse model carrying three disease causing mutations (Martin-Sanchez A et al., 2021). Therefore we hypothesize that already at six-months old, APPNL-F animals present depressive-like behavior and are more anxious compared to wild-type controls.

2. Understanding the astroglial contribution to such neuronal dysfunctions

A crucial astrocytic function is the uptake of glutamate by specific transporters located at process in the vicinity of the synaptic cleft. Glial Fibrillary Acidic Protein (GFAP), one of the most used astrocytic markers, GFAP is believed to be used as an anchor for these transporters (Sullivan SM et al., 2007) and have been shown to be altered in neurodegenerative disease (for review (Middeldorp J and Hol EM, 2011)). In line with this observations, our preliminary data have shown GFAP reduction in six-months old APPNL-F mice, associated with a reduction of complexity and branching (Figure 2), suggesting alterations of astrocytic functions. In line with a reduction of astrocytic complexity, we expect a reduction in glutamate uptake by astrocytes, leading to an increase of extracellular glutamate concentrations in APPNL-F mice. To test this hypothesis, we will use electrophysiology to record glutamate currents (Srivastava I et al., 2020). Glutamate transporter currents (arising from co-transport of ions during glutamate uptake) will be recorded from patch-clamped astrocytes in acute hippocampal slices. We hypothesize that glutamate transporter currents are reduced in six-months old APPNL-F mice compared to wild-type controls.

3. Identifying innovative pharmacological targets

To date, no disease-modifying treatment have been proposed for Alzheimer’s disease. It is therefore essential to identify new pharmacological targets for treatment. Brain hypercholesterolemia is associated to higher risks of developing AD (Kivipelto M and Solomon A, 2006). A recent study has shown an increased and sustained long term potentiation (LTP) in mice with high 27-hydroxycholesterol levels, similar to what we observed in six-months old APPNL-F animals (Loera Valencia R et al., 2021). We will thus explore lipid composition in six-months APPNL-F and we hypothesize that cellular lipid composition is already altered at young age. If cholesterol proportion is indeed affected, therefore associated to electrophysiological perturbations, this will open up for new drugs targeting this system. Cholesterol concentrations will be examined with an ELISA kit whereas using a specific dye such as the filipin III, a fluorescent antibiotic that binds sterols, we will study whether cholesterol proportions are more important in neurons and/or astrocytes from APPNL-F mice compared to wild-type controls. We previously observed an increased and maintained LTP when astrocytic glutamate transporters were blocked. Interestingly, we showed that a transient blocking of NMDA receptors could correct this synaptic mistuning (Juarez EV et al., 2022). We believe that such blocking by non-anesthetic dose of ketamine (5mg/kg) would in part correct the synaptic mistuning observed at young age. To a larger extent, we will investigate the effect of one unique injection of ketamine on social memory and depressive-like behavior (see part 1). We expect here a very mild effect of this MNDA receptors antagonist and sought at investigating the effect on neuronal activity and behavior of repeated administration. We propose here a new hypothesis saying that neuronal impairement at young age would contribute, at least in part to the amyloid depositions observed at later stages. As a consequence, we would like to investigate if either single injection or repeated injections of ketamine would also affect the kinetic of amyloid deposition in APPNL-F animals. As described in the literature, APPNL-F mice develop Aβ plaques at the age of nine months, thus we expect that ketamine would delay Aβ depositions.

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Benjamin Portal
Senast uppdaterad: 2021-03-09