Cellular Neurobiology

Responsible: 

Carme Solà Subirana

Researcher

Neuroinflammation, in which glial cells are mainly involved, has been repeatedly suggested to play a key role in the development of most neurodegenerative diseases. Glial activation is a process occurring in the presence of neuronal damage, involving morphological changes as well as changes in the expression of several molecules in astrocytes and microglia. It remains to be established if glial activation is a consequence of neuronal degeneration or is a previous phenomenon.
The main objective of the Cellular Neurobiology Group is to obtain information that could help to develop new strategies to contribute to the prevention and improvement of neurodegenerative processes occurring in the presence of chronic glial activation, using appropriate cellular and animal models. We are studying the implication of certain transcription factors (C/EBPs and NF-?B) and other proteins (p21 Cip1, CD200, CD200R, TREM) in the process of glial activation and its derived neurotoxicity. Our hypothesis is that the modulation of the function of these proteins may be a target to act against neuroinflammation and neuronal damage occurring in neurodegenerative diseases. 
We perform in vitro and in vivo studies using experimental animal, primary cell cultures (mixed glial cell cultures, enriched microglial, astroglial or neuronal cultures, mixed neuron-glia cultures) and cell lines. We are expertise in cytological, histological, biochemical, and molecular and cellular biology techniques.

Key words: Glia, Microglia, Astrocytes, Glial activation, p21 Cip1, C/EBPs, CD200, CD200R, TREM, Neuroinflammation, Neuroprotection, Glial cell cultures, Alzheimer, ALS.

Projects in course:

1.- Excitotoxic mechanisms, neuroinflamatory response and seric factors in experimental and human amyotrphic lateral sclerosis (Fundació La Marató de TV3. TV063031, IP: Joan Serratosa). 
Amyotrophic lateral sclerosis (ALS) is a dramatic neurodegenerative disease. Neurologists do not have any treatment giving a satisfactory improvement of its fatal course. From the pathogenetic point of view, the disease is still enigmatic in many aspects. There are several theories for ALS pathogenesis; none of them are mutually exclusive. We propose to develop a research addressed to analyze the influences of mutated SOD1 expression on the impact of glial cells on motoneuron survival.
We hypothesize that the expression of mSOD1 leads to functional changes in glial cells and that some of these changes may potentially exert negative effects on neuronal survival. Our objectives are:
a) To characterize the microglial response after LPS treatment in order to analyze whether mutant SOD1 mice have exacerbated glial activation in comparison with wild-type mouse microglia. To this end, we will determine the release of nitric oxide (NO) and tumor necrosis factor alpha (TNF?), the nuclear translocation of nuclear factor kappa B (NF-? B), the increase of the transcription factor C/EBP?, C/EBP? i C/EBP? and the increase of p21Cip1. All these compounds take part in the glial neuroinflammatory response. b) To study the effect of culture medium conditioned by LPS treated glial cells from mSOD1 and wild-type on MN viability. d) To inhibit, pharmacologically or through siRNA, the above mentioned factors and to study, in each case, the effect of such inhibition on neuronal viability.

2.- Is C/EBP? a target to attenuate the neuroinflammatory response associated with neurodegenerative disorders? (FIS, PI0704. IP: Josep Saura).

The transcription factor C/EBP? is an important regulator of gene expression in inflammation. Our working hypothesis is that C/EBP? plays also a key role in glial activation and that C/EBP? inhibition may result in an attenuated and less neurotoxic glial activation. Using systemic injection of lipopolysaccharide we have recently reported for the first time the in vivo expression of C/EBP? in activated glial cells. This result led us to the first objective of this project: to study whether C/EBP? expression in activated glial cells occurs in human neurological disorders and in their animal models. The second objective of this project is to study the role of C/EBP? in glial activation and the consequences of its inhibition. In order to accomplish this goal we propose:
In vitro studies of C/EBP? inhibition in glial cells using three experimental approaches: RNA interference, overexpression of the dominant negative C/EBP? isoform LIP and glial cultures from C/EBP? knockout mice. We will study the effects of C/EBP? inhibition on these aspects of glial activation: proinflammatory gene expression, neurotoxicity induced by activated glial cells, phagocytosis and proliferation. 
In vivo studies using microglial- or astroglial-specific C/EBP? deficient mice. The generation of these mice is part of this project. We will study the response of these animals in models of Parkinson’s and Alzheimer’s disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. 

3.- Glial activation inhibition as therapeutic target in neurodegenerative diseases (FIS, PI081396. IP: Carme Solà).

The main objective of this research project is to study the role of CD200, CD200R and TREM-2 in the modulation of the inflammatory response in microglial cells. Our hypothesis is that the signal mediated by CD200R and TREM-2 microglial receptors, which in normal conditions maintains under control the inflammatory response in microglial cells, is altered in neurodegenerative processes and its manipulation may result in the inhibition of glial activation/neuroinflammation and the derived neurotoxicity. We will study: 1) which stimuli regulate the expression of these proteins; 2) neuroinflammation markers regulated by these proteins; 3) the consequences of the inhibition or the activation of CD200, CD200R and TREM-2 in neuronal viability, in the absence and in the presence of neuroinflammation; 4) the involvement of these proteins in the mechanism of action of neuroprotective agents with anti-inflammatory properties, and 5) possible alterations in the expression of these proteins in the presence of neuronal damage in vivo, both in experimental models and in the post-mortem human brain affected by neurodegenerative diseases. In vitro and in vivo studies will be performed, and experimental animals and post-mortem human brain will be considered. We will use cytological and histological, biochemical, and molecular and cellular biology techniques.