Dynamic and functional evaluation of perisomatic inhibition in the hippocampal circuit during normal and pathological development in mice in vivo

Arnaldo Ferreira Gomes da Silva – Soutenance de thèse

Early activity in the developing brain Lab

Abstract

The hippocampus is an essential structure for learning processes and memory, including emotional and social spheres. The functioning of this neuronal circuit is based on complex interactions between excitatory glutamatergic pyramidal cells and various types of inhibitory GABAergic interneurons. The precise roles performed by interneurons subtype is poorly understood because it is very challenging to study the inhibitory function of specific interneurons in vivo. Alterations of synaptic interactions between pyramidal cells and hippocampal interneurons also underlies many pathologies such as epilepsy, autism, or Alzheimer’s disease.  This thesis work focuses on the development of perisomatic inhibitory function and on alterations in the hippocampal circuit and behavioral phenotype associated with neurodevelopmental disorders in mice.

Among the different types of interneurons, those whose axons project onto the cell bodies (perisomatic inhibition) of pyramidal cells are particularly effective in blocking action potentials of their target cells. This is the reason why they are considered to play an important role not only in the coding of information (by controlling which cell is able to discharge or not) but also in the balance of the circuit, to prevent reciprocal excitation between pyramidal cells from degenerating into epileptic seizure. The effectiveness of perisomatic inhibition depends directly on Cl- electrochemical gradient, i.e. the combination of the membrane potential and Cl- distribution across the membrane of the target neuron. However, these parameters are constantly changing during neuronal activity, and it has even been shown that the Cl- gradient can be reversed, resulting in paradoxically excitatory GABAergic transmission. This phenomenon, which contribute to the development of immature neuronal circuits, is also considered to be a major source of disruption of neuronal circuits in various pathologies such as epilepsy, autism or schizophrenia. It is therefore a field of research with direct clinical implications. The first and main part of my thesis consisted in the evaluation of this hypothesis by a new approach, direct and non-invasive, in natural conditions, in vivo, which had not been carried out until now due to the lack of suitable technical solution. On the basis of sophisticated electrophysiological recordings on anaesthetised or behaving animals, I was able to quantify perisomatic GABAergic transmission during normal development and in several models of autism spectrum disorders and mental retardation (Vangl2-KO, Dp1Yey, FMR1-KO, BTBR, VPA mice). My results indicate the expression of unexpected alterations in perisomatic inhibitory transmission under these conditions.

Another fundamental goal is to characterise the behavioural alterations associated with neural dysfunction. Many standardised tests are commonly used for a quick and efficient evaluation of the main cognitive, motor and emotional components, but recent technological advances and the growing interest in a less reductive description of behaviour have strongly contributed to the development of a more ethological approach of behavioural phenotyping. Thus, in the second part of my thesis, I contributed to the validation of a new behavioural phenotyping device that allows, through the fine characterisation of temporal dynamics of movements (grooming, locomotion, cardio-respiratory rhythms…), to detect the expression of motor and emotional alterations in neurodevelopmental disorders.

Jury

Pascal Branchereau – Président et Rapporteur – INCIA,  Bordeaux
Sabine Lévi – Rapportrice – Institut du Fer à Moulin, Paris
Hélène Marie – Examinatrice – IPMC-Sophia-Antipolis, Valbonne
Michel Picardo – Examinateur – INMED, Marseille
Xavier Leinekugel – Directeur de thèse – INMED, Marseille

Inmed meeting room – Friday 16 December 2022 at 2pm