Supervisor: Andreas FRICK
Title: The role of intrinsic neuronal excitability for Prelimbic network function
The goal of this work was a characterization of the cellular identity of Layer 5 neurons of the prelimbic (PL) subarea of the medial prefrontal cortex (mPFC) in mice. In performing this analysis, we considered the intrinsic properties of these neurons, their morphology, connectivity and finally their transcriptional profile.
In the first part of this study, we considered the question of how the expression of the receptors a of important neuromodulatory molecule (dopamine) can be used, in addition to other criteria, for the characterization of cell-type identity. In the PL, two major receptor types, Dopamine 1 (D1R) and 2 (D2R) receptor have been described. We characterized the cellular identity of these neurons in wild-type (WT) mice and then used these findings as a reference for the characterization of molecular and cellular defects in the PL of Fmr1KO, a model for fragile X syndrome (FXS) and autism spectrum disorder (ASD).
To do this, we analyzed the intrinsic electrical properties of these neurons and performed a clustering of neurons based on these intrinsic properties. We analyzed the morphology of these neurons, as well as their principal projections to other brain areas. In addition, RNA sequencing analysis revealed more than 500 genes differently expressed between D1R and D2R neurons. Further analysis of the transcriptional profile of these neurons revealed differences based on a number of different categories such as the expression of ion channels, transcription factors and cell adhesion molecules. This data then served as a reference for the characterization of molecular and physiological changes in the PL in FXS/ASD. FXS is the most common inherited cause of intellectual disability and the most frequent genetic cause of autism. FXS is characterized by learning and memory deficits, repetitive behavior, seizures and hypersensitivity to sensory (e.g. visual) stimuli. Dopamine modulation is altered in this model and it was thus pertinent to determine how changes to this important modulatory system might impact on cell identity in FXS. We observed differences in intrinsic properties between D1R and D2R neurons. However, these changes showed important differences from those observed in WT mice. These differences might be explained by alterations in mRNA expression in these two neuronal populations in Fmr1KO mice. In particular, our findings point to an overexpression of genes particularly in D1R population of Fmr1KO mice.
In the second part of this study, we turned our attention to changes in the intrinsic electrophysiological properties of amygdala-projecting PL during early encoding of contextual fear memories. We used contextual fear conditioning together with retrograde tracing and whole-cell electrophysiological recordings of labeled pyramidal neurons in adult 2-3 month old male C56BL/6J mice. We show that neurons projecting to the amygdala display learning-dependent changes in neuronal excitability during early encoding of contextual fear conditioning, but not at a remote time-point. In addition, we demonstrated that manipulation of the intrinsic properties of this specific population during the early phases or memory encoding (but not during remote phases) lead to alterations in fear memory recall at a remote time-point.
Keywords : Prefrontal cortex, Dopamine, Ion channels, Fragile X syndrome, Memory
Dr. Pietropaolo, Susanna – Bordeaux, FRANCE
Prof. Ramaswami, Mani – Dublin, IRELAND Rapporteur
Dr. Coutureau, Etienne – Bordeaux, FRANCE
Dr. Schubert, Dirk – Nijmegen, NETHERLANDS