Project Details
Projekt
Cellular mechanisms to establish neuronal homeostatic setpoints during an embryonic critical period.
Applicant
Dr. Niklas Krick
Subject Area
Developmental Neurobiology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 493150079
Functional stability of many organ systems, including that of the central nervous system, is achieved by virtue of homeostatic setpoints to which the system works to return following disturbances. When homeostatic setpoints of nervous systems are set during development is not well understood, though a recent study points to so-called ‘critical periods’, associated with the emergence of coordinated network activity. It is during critical periods that patterns of network activity lead to the specification of neuronal attributes, including excitability and synaptic transmission properties. Importantly, activity perturbations during the critical period lead to aberrant neuronal properties and thus suboptimal, unstable networks, thought to underlie some neuro-developmental and psychiatric conditions in humans. Why critical period errors cannot later be corrected by persistent plasticity mechanisms has remained unresolved. The proposal will test the hypothesis that neuronal homeostatic setpoints are specified during the critical period. This has now become possible with the identification of a critical period in an exceptionally tractable model system of limited complexity, the locomotor network of the fruit fly larva, Drosophila melanogaster. Specifically, this experimental model allows us to apply precisely defined activity perturbations during the critical period, across a gradient of severity, targeted to specific neurons of known connectivity and function. Thus, changes in critical period experiences at the single cell level can for the first time be systematically analysed with respect to neuronal homeostatic setpoints. Proof of concept experiments have already established that such manipulations cause lasting changes in synapse number, terminal growth and physiological properties, compatible with changes in homeostatic setpoint.We will thus address two interlinked questions. The first is to identify the cellular substrates that define the homeostatic setpoint; for example, synaptic terminal size, synapse number, connectivity and/or neuronal excitability within neurons of the central nervous system. This will reveal how such setpoints are established, e.g. via analogue or digital tuning of structural and physiological parameters. Secondly, we will investigate the mechanism by which activity experiences during the critical period are converted into lasting changes of those cellular substrates. Taking a candidate approach, the focus will be on the small, non-redundant family of voltage gated calcium channels, which I have recently identified as required for homeostatic adjustments.In summary, this proposal will take advantage of a new experimental model system that now allows us to study unresolved questions fundamental to our understanding of nervous system development and function.
DFG Programme
WBP Fellowship
International Connection
United Kingdom
