Head: Prof. Gerardo Biella

Contributors: Paolo Spaiardi; Francesca Talpo; Francesca Raffin

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

HD is a neurodegenerative disease caused by an autosomal dominant mutation in the IT-15 gene coding for the huntingtina protein (Htt). The role of Htt is still unknown. The protein is ubiquitous, essential for embryogenesis, development and neuronal 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) that is toxic to neurons and causes extensive loss of brain neurons, especially at the cortical and striatal levels. mHtt results, in addition to neuronal death in the last stage of the disease, in progressive alterations in the morphology, excitability, and synaptic properties of cortical pyramidal neurons (CPNs) and middle spiny neurons (MSNs). Thus, the early behavioural and cognitive symptoms of HD precede neuronal death rather than being a consequence of it. Decoupling of connectivity and plasticity at CPN/MSN synapses and excitotoxicity, mainly mediated by alterations of NMDA receptors, seem crucial in the pathogenesis and progression of HD. Using multidisciplinary approaches (behavioural, electrophysiological etc.), we intend to analyse the progressive

Referees: Prof. G. Biella, P. Spaiardi and F. Talpo.

Collaborators: E. Cattaneo, C. Zuccato and M. Valenza (UNIMI)

2. Functional evaluation of medium 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 characterisation of a specific class of striatal neurons, the medium spiny neurons (MSN). Using a specific differentiation protocol from human embryonic stem cells (hES, line H9), cultures of MSNs will be obtained. We are also interested in the electrophysiological characterisation of striatal neurons differentiated from induced pluripotent stem (hiPS) cells derived from fibroblasts of healthy and diseased subjects. In this way, it is possible to model Huntington’s disease in vitro and make an important 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 assess the degree of in vivo differentiation and the ability to restore synaptic circuits altered in the disease.

Referees: Prof. G. Biella, P. Spaiardi and F. Talpo

Collaborators: E. Cattaneo, P. Conforti and 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 medial temporal lobe memory system. This project focuses on the study of the mechanisms that govern the intrinsic excitable properties of neurons in the hippocampal region, their functional implications for communication between the parahippocampal region and the hippocampus, and the neuromodulatory systems that control them. In particular, the following will be studied: 1) the intrinsic membrane mechanisms that determine the specific discharge properties of neurons in the entorhinal cortex (EC) and perirhinal cortex (PRC); 2) the neuromodulation operated by IGF2 and oxytocin on basic synaptic properties and synaptic plasticity; 3) the regulatory mechanisms by which the PRC is able to operate its characteristic function of selecting incoming signals directed towards the hippocampus through the EC.

Referees: Prof. G. Biella, P. Spaiardi and F. Talpo

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

4. SPeye

To date, there are no cures for certain diseases that impair retinal function. In collaboration with national INFN-affiliated groups, a project is being developed to create an implantable artificial retina based on silicon PMs (silicon photomultipliers). SPeye proposes an innovative approach based on the sub-retinal implantation of a newly developed array of silicon detectors with internal amplification: silicon photomultipliers (silicon PM or SPAD). These devices will enable better visual performance with reduced power consumption and will provide several advantages in the final implantation stage. Our research group aims to evaluate the biocompatibility of these devices and their eficacy in activating cells when activated by light stimulation.

Referees: Prof. G. Biella, P. Spaiardi and F. Talpo

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