title: Functional diversity of the medial septal GABAergic interneurons
Creators: name: Saidov, Khalid
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2025

description: Accumulated findings have shown an impressive heterogeneity of the medial septal (MS) neurons as well as have uncovered their anatomical interconnectivity and the functional interplay with other brain areas that are crucially involved in different behaviours. Particularly, these studies have discovered that one of the major cellular subtypes of the MS is GABAergic interneurons that form a dense intraseptal cellular network with other types of neuronal populations in the MS and mainly project to the parahippocampal formation and the hippocampus (HPC) that are traditionally thought to be associated with memory and cognition. On the other hand, a large amount of research that performed for last decades have demonstrated the functional importance of the MS at the behaviour level, from sensorimotor integration to memory-guided behaviours. Recent studies have revealed that main sources of the MS GABAergic neurons are parvalbumin (PV+) and calbindin (CB+) positive neurons that both target the HPC and the entorhinal cortex (EC). Specifically, these studies have demonstrated the cell-type specific targeting and distinct physiological properties of targets for the major types of the MS GABAergic neuronal populations, their involvement in behavior and cognition and aimed to uncover the functional roles of these cells. Despite accumulated findings, the specific contribution of distinct major MS GABAergic neuronal populations (specifically, PV+ and CB+) and their projections to prominent target brain areas in memory-guided behavior was not systematically studied and remains largely unclear. I have explored this question in this thesis from three sides. Firstly, I have evaluated the functional effect for inactivation of two distinct GABAergic neuronal types in the MS (specifically, PV+ and CB+) during memory-guided behavior. Secondly, I have analyzed whether the targeting the MS PV+ and CB+ GABAergic neurons to the dorsal hippocampus (dHC), the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC) differential or not in terms of distribution for projections of these distinct cell types in same brain areas. Thirdly, I have examined the functional effect for selective inactivation of the MS PV+ and CB+ GABAergic projections to the dHC, the MEC and the LEC during retrieval of reward-associated spatial memory. To study these questions, I have performed chemogenetic silencing the MS PV+ and CB+ GABAergic neurons as well as chemogenetic inactivation of their terminals to the dHC and the EC via implanted cannulae during testing of transgenic mice on a spatial behavioral task (namely, on the eight-arm radial maze) and histological examination of their projections to the dHC, the MEC and the LEC. First, I have demonstrated the differential contribution of the MS PV+ and CB+ GABAergic neurons to different types of memory (specifically, working and reference memory) that form on the eight-arm radial maze. Thus, inactivation of the PV+ cells impaired reference memory, whereas silencing the CB+ neurons led to deficit in working and reference memory in the used task. These findings have shown a segregation for the function of two MS GABAergic neuronal populations in reward-associated spatial memory on the eight-arm radial maze. Second, I have revealed the differential targeting the MS PV+ and CB+ neurons along the septo-hippocampal and the septo-entorhinal pathways. Thus, PV+ projections are denser than CB+ in the dHC, whereas in the MEC, the broad distribution of PV+ and CB+ projections is similar. There are more CB+ ones in the LEC in comparison with the sporadic PV+ ones. Finally, I have uncovered asymmetric functional contributions for terminals of these two differentially projecting to the dHC, the MEC and the LEC neuronal populations to behavioral performance on the eight-arm radial maze. Thus, silencing the MS PV+ projections to the dHC and the MEC led to deficit in reference but not working memory on the eight-arm radial maze, whereas inactivation of the MS CB+ terminals to the MEC impaired both working and reference memory. Selective chemogenetic silencing the MS CB+ projections to the dHC did not affect spatial memory. Working and reference memory also remained intact after the inactivation of the MS PV+ and CB+ terminals to the LEC. Based on previous research and results of the present study, it might be supposed that the different contribution of the PV+ and CB+ MS GABAergic neurons to memory-guided behavior is determined not only by a density of anatomical projections to main target areas but also by the cell-type heterogeneity of targeted cells and their electrophysiological properties. Taken together, findings of this thesis elicit the distinct functional mode for action of the PV+ and CB+ MS GABAergic cells and expand understanding the functional diversity of behaviorally tuned neurons.