Prof Matthias Landgraf

We are interested in understanding how nervous systems develop and how function emerges. One of the central questions is: How does nature deal with what it cannot predict, such as changes in (seasonal/global) temperature. As a model system we use the locomotor network of the Drosophila (fruit fly) embryo and larva, as this allows us to work with identified connecting nerve cells to which we can return time and again. As experimental approaches we use state of the art genetics, imaging, electrophysiology and behavioural analysis.

Critical periods of nervous system development: Nervous systems, like many biological systems, manifest appreciable levels of variability. How can networks reliably generate robust behaviours in the face of inherent cell-to-cell variability? When neural networks become functional, their constituent cells need to adjust to each other, so that they can work well together in order to generate appropriate behavioural outputs. These tuning phases are called 'critical periods' because perturbations during a critical period usually cause network instability (leading to seizures and other network malfunction). Importantly, critical period-induced errors persist longterm. This presents another unresolved mystery, namely how is it that such errors cannot be corrected by the many plasticity mechanisms that nerve cells have at their disposal? For example, a transient 2-hour heat stress experience during the embryonic critical period causes lasting maladjustment of the nervous systems. This manifests as altered behaviour and inherent network instability, which causes seizure susceptibility to seizures.

In collaboration with Prof. Richard Baines, University of Manchester, we have been investigating (Wellcome Trust and BBSRC funded) the changes that critical period perturbations cause in the network (e.g. structural) and the properties of nerve cells (e.g. excitability). One line of thought is that critical periods define homeostatic setpoints. A change in homeostatic setpoint would immediately explain why a critical period-induced change in properties cannot be later 'corrected' by other plasticity mechanisms.

Funded by EMBO, we have discovered that mitochondrial (Reactive Oxygen Species) and metabolic signals (HIF-1alpha) instruct lasting changes in cellular metabolism and gene expression. Now, with renewed BBSRC funding, we are exploring the underlying mechanisms that define the developmental window of the critical period, and how such changes in cellular properties are maintained well into late life.

Key publications: 

Sobrido-Cameán D, Coulson B, Miller M, Oswald MCW, Pettini T, Bailey DMD, Baines RA, Landgraf M. (2025) Mitochondrial ROS and HIF-1α signaling mediate synaptic plasticity in the critical period. PLoS Biol. 23(8):e3003338. doi: 10.1371/journal.pbio.3003338. 

Corke J, Huertas-Radi M, Landgraf M, Baines RA. (2025). Maturation of GABAergic signalling times the opening of a critical period in Drosophila melanogaster. Sci Rep. 15(1):40285. doi: 10.1038/s41598-025-24116-2. 

Hunter I, Coulson B, Pettini T, Davies JJ, Parkin J, Landgraf M, Baines RA. (2024). Balance of activity during a critical period tunes a developing network. Elife. 12:RP91599. doi: 10.7554/eLife.91599. 

Sobrido-Cameán D, Oswald MCW, Bailey DMD, Mukherjee A, Landgraf M. (2023). Activity-regulated growth of motoneurons at the neuromuscular junction is mediated by NADPH oxidases. Front Cell Neurosci. 16:1106593. doi: 10.3389/fncel.2022.1106593. 

Giachello CNG, Hunter I, Pettini T, Coulson B, Knüfer A, Cachero S, Winding M, Arzan Zarin A, Kohsaka H, Fan YN, Nose A, Landgraf M, Baines RA. (2022). Electrophysiological Validation of Monosynaptic Connectivity between Premotor Interneurons and the aCC Motoneuron in the Drosophila Larval CNS. J Neurosci. 42(35):6724-6738. doi: 10.1523/JNEUROSCI.2463-21.2022.

Giachello CNG, Fan YN, Landgraf M, Baines RA. (2021). Nitric oxide mediates activity-dependent change to synaptic excitation during a critical period in Drosophila. Sci Rep. 11:20286. doi: 10.1038/s41598-021-99868-8. 

Dhawan S, Myers P, Bailey DMD, Ostrovsky AD, Evers JF, Landgraf M. (2021). Reactive Oxygen Species Mediate Activity-Regulated Dendritic Plasticity Through NADPH Oxidase and Aquaporin Regulation. Front Cell Neurosci. 2021; 15: 641802. DOI: 10.3389/fncel.2021.641802.

Oswald MCW, Brooks PS, Zwart MF, Mukherjee A, West RJH, Giachello, CNGMorarach K, Baines RA, Sweeney ST and Landgraf M. (2018). Reactive Oxygen Species Regulate Activity-Dependent Neuronal Structural Plasticity.  eLife, 7. DOI: 10.7554/eLife.39393.

Zwart MF, Pulver SR, Truman JW, Fushiki A, Fetter, RD, Cardona A, Landgraf M. (2016). Selective Inhibition Mediates the Sequential Recruitment of Motor Pools. Neuron 91(3):615-628.  DOI: 10.1016/j.neuron.2016.06.031.  

Couton L, Mauss AS, Yunusov T, Diegelmann S, Evers JF, Landgraf M (2015). Development of connectivity in a motoneuronal network in Drosophila larvae. Curr Biol 25: 568–576, 2015. DOI: 10.1016/j.cub.2014.12.056.  (see also Dispatch by Sternberg JR, Wyart C. Neuronal wiring: linking dendrite placement to synapse formation. Curr Biol 25: R190–1, 2015.)