Our research focuses on changes in neurotrophin receptors (NTR) expression pattern as an early marker for neuroadaptation precurring neuropsychiatric disorders. We propose that NTR imbalance may be a pharmacological target for the modulation of underlying molecular mechanisms. The research focus is on p75, the first NTR to be discovered but also the less known in terms of functional role in adult CNS. This paper presents an overview about the multidisciplinary experimental approaches set up in our laboratory for studying p75 role in neuroadaptation in CNS. Our major working hypothesis concern several p75 properties such as, i) expression changes, ii), downstream activated intracellular signalling mechanisms, iii), trafficking and, iv), p75 putative role in synaptic plasticity processes, such as controlling neurotransmitter release from cholinergic basal forebrain (BF) neurons. These scopes are pursued by using the following techniques and molecular tools: a) ex-vivo immunohistochemistry on rat brain tissue, in-vitro cultured b) cell lines and c) primary neurons, d) p75-GFP fusion protein construct, and, d) in-vitro model of cholinergic neurons from rat embryonic BF. We found that p75 is selectively expressed only in rat adult BF nuclei, and in-vitro cultured primary BF neurons. In other cell cultures - neuroblastoma, cortical and hippocampal primary cultures - we were able to study receptor trafficking and subcellular distribution by transfecting the p75-GFP construct. A functional characterization was performed in in-vitro cultured primary BF neurons. We found that prolonged neurotrophins (NGF, BDNF) and KCl treatments differently influenced i), p75 expression and ii), acetylcholine release in/from the cholinergic population of BF cultures. We have therefore completed the validation of different p75 receptor system models, showing how pharmacological stimulations may differentially affect p75 expression, distribution and function. Future directions of our work will be the use of pro-neurotrophins (pro-NTs), as potential stimuli inducing neuroadaptation. In fact, our hypothesis is that pro-NTs, which specifically bind p75 and are active in adult brain, may modulate through p75 activation not only apoptotic responses, but also neuroadaptative processes in mature neurons.

The role of neurotrophin receptor p75 in rat CNS: an integrative approach

FORMAGGIO, Elena;DALFINI, Anna;CHIAMULERA, Cristiano;FUMAGALLI, Guido Francesco
2007-01-01

Abstract

Our research focuses on changes in neurotrophin receptors (NTR) expression pattern as an early marker for neuroadaptation precurring neuropsychiatric disorders. We propose that NTR imbalance may be a pharmacological target for the modulation of underlying molecular mechanisms. The research focus is on p75, the first NTR to be discovered but also the less known in terms of functional role in adult CNS. This paper presents an overview about the multidisciplinary experimental approaches set up in our laboratory for studying p75 role in neuroadaptation in CNS. Our major working hypothesis concern several p75 properties such as, i) expression changes, ii), downstream activated intracellular signalling mechanisms, iii), trafficking and, iv), p75 putative role in synaptic plasticity processes, such as controlling neurotransmitter release from cholinergic basal forebrain (BF) neurons. These scopes are pursued by using the following techniques and molecular tools: a) ex-vivo immunohistochemistry on rat brain tissue, in-vitro cultured b) cell lines and c) primary neurons, d) p75-GFP fusion protein construct, and, d) in-vitro model of cholinergic neurons from rat embryonic BF. We found that p75 is selectively expressed only in rat adult BF nuclei, and in-vitro cultured primary BF neurons. In other cell cultures - neuroblastoma, cortical and hippocampal primary cultures - we were able to study receptor trafficking and subcellular distribution by transfecting the p75-GFP construct. A functional characterization was performed in in-vitro cultured primary BF neurons. We found that prolonged neurotrophins (NGF, BDNF) and KCl treatments differently influenced i), p75 expression and ii), acetylcholine release in/from the cholinergic population of BF cultures. We have therefore completed the validation of different p75 receptor system models, showing how pharmacological stimulations may differentially affect p75 expression, distribution and function. Future directions of our work will be the use of pro-neurotrophins (pro-NTs), as potential stimuli inducing neuroadaptation. In fact, our hypothesis is that pro-NTs, which specifically bind p75 and are active in adult brain, may modulate through p75 activation not only apoptotic responses, but also neuroadaptative processes in mature neurons.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/311726
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