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Biophysics of Ion Channels and Neurophysiology Laboratory

Biofisica dei Canali Ionici e Neurofisiologia

Referent: Prof. Gerardo Biella

Co-workers: Paolo Spaiardi; Francesca Talpo; Francesca Raffini; Nicolas Castagno


1. Analysis of striatal and hippocampal synaptic circuits in animal models of Huntington's disease (HD)

HD is a neurodegenerative disorder caused by an autosomal dominant mutation in the IT-15 gene that codes for the huntingtin protein (Htt). The role of Htt is still unknown. The protein is ubiquitous, essential for embryogenesis, neuronal development and survival, and is also involved in synaptic activity. Expansion of the CAG triplet in exon 1 of the IT-15 gene (> 36 repeats) generates a mutated form of Htt (mHtt) which is toxic to neurons and causes extensive loss of brain neurons, especially in the cortical and striatal levels. mHtt determines, in addition to neuronal death in the last stage of the disease, also progressive changes in the morphology, excitability, and synaptic properties of cortical pyramidal neurons (CPNs) and medium spiny neurons (MSNs). Therefore, the first behavioral and cognitive symptoms of HD precede neuronal death rather than being a consequence of it. The decoupling of connectivity and plasticity at the level of the CPN / MSN synapses and excitotoxicity, mainly mediated by alterations of NMDA receptors, seem crucial in the pathogenesis and progression of HD. Using multidisciplinary approaches (behavioral, electrophysiological etc.), we intend to analyze the progressive destructuration of excitatory cortico-striatal synapses in mouse models of HD, both in the pre-symptomatic and in the symptomatic stages of the disease. The experiments will be performed on thin sections of ex vivo brain and/or on primary cultures.

Referents: Prof. G. Biella, P. Spaiardi e F. Talpo.

Collaborations: E. Cattaneo, C. Zuccato e M. Valenza (UNIMI)


2. Functional evaluation of middle spiny neurons of the striatum differentiated from embryonic stem cells and reprogrammed from fibroblasts of patients with Huntington's disease.

This research project focuses on the functional characterization of a specific class of striatal neurons, the middle spiny neurons (MSN). Through a specific differentiation protocol from human embryonic stem cells (hES, H9 line), MSN cultures will be obtained. We are also interested in the electrophysiological characterization of differentiated striatal neurons starting from induced pluripotent stem cells (hiPS), derived from fibroblasts of healthy and diseased subjects. In this way, it is possible to model Huntington's disease in vitro and provide a relevant contribution to the understanding of the multiple and still unknown molecular mechanisms underlying neurodegeneration. Stem cell-derived neurons will be transplanted into rodent models of HD disease. Functional investigations will be conducted to evaluate the degree of differentiation in vivo and the ability to restore the synaptic circuits altered in the disease.

Referents: Prof. G. Biella, P. Spaiardi e F. Talpo

Collaborations: E. Cattaneo, P. Conforti e D. Besusso (UNIMI), A. Buffo (UNITO)


3. Mechanisms and neuromodulation of membrane excitability in neurons of the hippocampal region

The parahippocampal cortices (PHCs) establish bidirectional synaptic interactions with the hippocampus that are of fundamental importance for the memory and spatial orientation functions of the memory system of the medial temporal lobe. This project is focused on studying the mechanisms that govern the intrinsic excitable properties of neurons in the hippocampal region, their functional implications for communications between the parahippocampal region and the hippocampus, and the neuromodulatory systems that control them. In particular, we will study: 1) the intrinsic membrane mechanisms that determine the specific firing properties of neurons in the entorhinal (EC) and perirhinal (PRC) cortex; 2) the neuromodulation operated by IGF2 and oxytocin on basic synaptic properties and synaptic plasticity; 3) the regulation mechanisms through which the PRC is able to operate its characteristic function of selecting the input signals directed to the hippocampus through the EC.

Referents: Prof. G. Biella, P. Spaiardi e F. Talpo

Collaborations: C. Alberini (NYU), C. Maniezzi (UNIMIB)


4. SPeye

To date, there are no treatments for some pathologies that compromise the functionality of the retina. In collaboration with national groups affiliated with INFN, a project is being developed to create an implantable artificial retina based on silicon PM (silicon photomultipliers). SPeye proposes an innovative approach based on the subretinal implantation of a recently developed silicon detector array with internal amplification: silicon photomultipliers (silicon PM or SPAD). These devices will allow to obtain better visual performances with reduced power consumption and will guarantee various advantages in the final stage of the system. Our research group aims to evaluate the biocompatibility of these devices and their effectiveness in activating cells when activated by light stimulation.

Referents: Prof. G. Biella, P. Spaiardi e F. Talpo

Collaborations: P. Cattaneo, M. Rossella (INFN-Pavia), S. Ramat, I. Cristiani, P. Malcovati (UNIPV-INFN), P. Massobrio (UNIGE-INFN)