General principles of structural maturation and integration of newly born granule cells in the hippocampal network studied by time-lapse imaging and computational models
Developmental Neurobiology
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Structural maturation and integration of neurons into functional networks is a highly dynamic process that requires plasticity on the level of generation, growth and adjustment of axons, dendrites and synapses. The hippocampal dentate gyrus is a unique brain structure, where new neurons are generated throughout life, a process called adult neurogenesis. Increasing evidence points to a substantial rate of ongoing acquisition of new neurons in the human dentate gyrus and its disturbance may be clinically relevant. Importantly, the hippocampus is associated with learning and memory formation, functional processes requiring synaptic plasticity including long term potentiation (LTP). In our project, we studied different forms of neuronal plasticity in the hippocampus, both in vitro, in vivo, and in silico. We studied structural maturation and integration of newly born dentate granule cells (GCs) in entorhino-hippocampal organotypic slice cultures (OTCs) under live-imaging conditions. Virally labeled GCs showed enhanced dendritic elongation and pruning of individual segments in days and even hours during maturation. The high level of dendritic dynamics depended on network activity, as local optogenetic stimulation enhanced maturation, whereas chronic blockade of synaptic activity prolonged maturation. An in depth computer-aided structural analysis of these in vitro findings with in vivo datasets from adult born GCs revealed a strikingly similar time course and characteristics of dendritic structural maturation. The phase of high dendritic dynamics in newly born neurons could be useful for regeneration and repair of neural networks following damage. We developed a novel experimental model of local brain damage in OTCs that resulted in the activation of adjacent newly born granule cells. Integration of new neurons requires synapse formation on dendritic spines and spine heads correlate with synaptic strength. Distribution of spine head sizes follows a lognormal-like distribution. We analysed spine size distribution in adult-born hippocampal GCs from rats with induced LTP in vivo and hippocampal CA1 pyramidal cells from Munc13-1/Munc13-2 knockout mice with completely blocked synaptic transmission. Computational modelling indicated that intrinsic synaptic plasticity is sufficient for generation, while intrinsic and extrinsic synaptic plasticity maintain lognormal-like distribution of spines. Induction of long-term synaptic plasticity and LTP in hippocampal GCs in vivo also affects the axon initial segment (AIS), the site of action potential initiation. Length and localization of the AIS are dynamic, modulated by afferent activity and contribute to the homeostatic control of neuronal excitability. Three-dimensional analysis of the AIS revealed a rapid structural plasticity of the AIS and its cisternal organelles to strong stimulation. In order to study the clinical relevance of altered synaptic activity and plasticity we analysed two mouse models with a lack of different members of the family of neuroligins (Nlgn) in vivo. Both, Neuroligin-3 and Neuroligin-4 are neuronal adhesion proteins that are important for synaptic organization and implicated in autism spectrum disorder (ASD). Electrophysiological recordings of GC field potentials indicate that interactions between different neuroligins may play an important role in regulating synaptic transmission. Together, our studies support evidence for the clinical relevance of dynamic changes of hippocampal GCs and the dentate neural network.
Publications
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Neuroligin-3 Regulates Excitatory Synaptic Transmission and EPSP-Spike Coupling in the Dentate Gyrus In Vivo. Molecular Neurobiology, 59(2), 1098-1111.
Muellerleile, Julia; Vnencak, Matej; Ippolito, Angelo; Krueger-Burg, Dilja; Jungenitz, Tassilo; Schwarzacher, Stephan W. & Jedlicka, Peter
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Increased Network Inhibition in the Dentate Gyrus of Adult Neuroligin-4 Knock-Out Mice. eneuro, 10(4), ENEURO.0471-22.2023.
Muellerleile, Julia; Vnencak, Matej; Sethi, Mohammad Valeed Ahmed; Jungenitz, Tassilo; Schwarzacher, Stephan W. & Jedlicka, Peter
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Skewed distribution of spines is independent of presynaptic transmitter release and synaptic plasticity, and emerges early during adult neurogenesis. Open Biology, 13(8).
Rößler, Nina; Jungenitz, Tassilo; Sigler, Albrecht; Bird, Alexander; Mittag, Martin; Rhee, Jeong Seop; Deller, Thomas; Cuntz, Hermann; Brose, Nils; Schwarzacher, Stephan W. & Jedlicka, Peter
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Structural plasticity of the axon initial segment in rat hippocampal granule cells following high frequency stimulation and LTP induction. Frontiers in Neuroanatomy, 17.
Jungenitz, Tassilo; Bird, Alexander; Engelhardt, Maren; Jedlicka, Peter; Schwarzacher, Stephan W. & Deller, Thomas
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Hippocampal damage through foreign body placement in organotypic cultures leads to plastic responses in newly born granule cells. Neural Regeneration Research, 21(3), 1142-1150.
Jungenitz, Tassilo; Frey, Lukas; Kirscht, Sophia; Schwarzacher, Stephan W. & Zepeda, Angélica
