TELETHON GRANT PROJECT 2019 N. GGP19281A - Dr.ssa Claudia Lodovichi - INTRACELLULAR CHLORIDE DYNAMICS IN AUTISTIC BRAIN: A BETTER UNDERSTANDING IS NEEDED FOR TAILORED CURES (DSB.AD004.261)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of neuroscience (IN)

Project manager

CLAUDIA LODOVICHI
Phone number: 049/7923220
Email: claudia.lodovichi@unipd.it

Abstract

Neuronal activity is finely tuned during sleep, wakefulness and cognitive and sensory tasks by the balancing act
of principal neurons and interneurons. This is particularly relevant in pathological conditions since it is gradually
emerging that a distortion of the dialogue between excitatory and inhibitory neurons is likely to be at the basis of
most, if not all, cognitive deficits. Inhibition shapes the activity of principal neurons playing a crucial role in
sensory cognition and learning. Fast GABA transmission relies on the activity of channel mainly permeable to
chloride and neuronal inhibition requires the influx of Cl- that hyperpolarizes the target neuron. A central tenet of
our understanding of synaptic inhibition is that GABAergic activity always results in chloride influx, except in the
early phases of development when intracellular chloride is high and GABA depolarizes the postsynaptic
neurons.
This picture is challenged by recent data obtained by the proponents: in the past several years we have
developed a novel technique that, for the first time, allows to measure intracellular chloride by means of two
photon imaging, and, by exploiting this breakthrough we have disco

Goals

We will study the regulation of Cl- by direct measurement of [Cl- ]i in two models of brain disorders caused by the loss of function of the genes Oligophrenin1 and PTEN. Furthermore, we will study the functional consequences of Cl- dysregulation by a combination of imaging and electrophysiology techniques. Finally, we will evaluate the effects of modulators of Cl- cotransporter by direct assessment of [Cl- ]i and of relevant electrophysiological properties. These data will provide a necessary, but still lacking, background to the use of these drugs for the treatment of cognitive deficits.
Cl- dysregulation can play a central role in brain disease etiology in two, non-mutually exclusive stages that will be studied in the first two aims of the proposal: a) during early development, when elevated [Cl- ]i plays an important role in neuronal migration, maturation and synaptogenesis and b) through lifetime since correct Cl homeostasis is essential for proper inhibitory feedback. In the third aim we will ascertain the effect of the blockade of Cl cotransporter on Cl heterogeneity, on cortical synchrony and computation.

Start date of activity

01/01/2020

Keywords

Autistic disorders

Last update: 23/05/2025