Project ID NS-MH2024_02

ThemeNS-MH

Co Supervisor 1A Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Centre for Developmental NeurobiologyWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

The role of NMDA receptors in the functional development of circuits for learning and memory

How do neuronal circuits wire together during development in the right place and at the right time? And what happens when this process is altered in neurodevelopmental disorders? In this project, we will explore the role of NMDA receptors (NMDARs) in the development of specific connections in the hippocampus, and identify how mutations in key NMDAR subunits affect learning and memory.

The role of neuronal activity in synapse and neuronal development remains controversial, but we have found that synaptic release of the excitatory neurotransmitter, glutamate, acts on NMDARs to regulate synapse formation. Loss of NMDAR function disrupts the development of specific synaptic connections in the hippocampus, a region critical for spatial learning. Moreover, loss of function mutations in NMDAR subunits are known to cause profound neurodevelopmental disorders, including intellectual disability and developmental delay.

In this project, we will specifically target loss of function of different NMDAR subunits at different developmental stages using inducible/conditional transgenic lines and apply behavioural tasks to understand when and how these early changes affect learning, focusing on the response to object novelty and familiarity. We will combine this with 2-photon imaging and electrophysiology in vivo, as well as 3D structural imaging, to identify how loss of function of NMDAR subunits at targeted developmental stages alters the structure and function of hippocampal neurons and synapses over development.

Techniques:
Inducible/conditional transgenic mouse lines, AAV injections
Learning/memory behavioural tasks
2-photon structural and functional imaging in vivo
Electrophysiology
Optional – optical clearing, 3D lightsheet structural imaging, connectivity tracing,

  • Year 1 objective – establish crosses, test impact on learning behaviour
  • Year 2 objective – learn imaging techniques to identify impact on neuronal structural development and activity patterns.
  • Year 3 objective – learn electrophysiology (in vivo and/or in vitro), characterise activity patterns/synaptic changes.
  • For 0+4, Year 4 objective – combine approaches to link functional changes to behaviour.

Representative Publications

Ellingford RA, Panasiuk MJ, Rabesahala de Meritens E, Shaunak R, Naybour L, Browne L, Basson MA, Andreae LC. Cell-type-specific synaptic imbalance and disrupted homeostatic plasticity in cortical circuits of ASD-associated Chd8 haploinsufficient mice. Molecular Psychiatry 2021; Jul;26(7):3614-24. doi: 10.1038/s41380-021-01070-9.

Andreae LC* and Burrone J. Spontaneous neurotransmitter release shapes dendritic arbors via long-range activation of NMDA receptors. Cell Reports, 2015; 10(6):873-82 Andreae LC* and Burrone J. The role of spontaneous neurotransmission in synapse and circuit development. Journal of Neuroscience Research, 2018; 96(3):354-9.

Chaloner FA and Cooke SF (2022) Multiple Mechanistically Distinct Timescales of Neocortical Plasticity Occur During Habituation. Frontiers in Neural Circuits. 15: 176. DOI: 10.3389/fncel.2022.840057.

Fong MF, Finnie PF, Kim T, Thomazeau A, Kaplan ES, Cooke SF*, Bear MF* (2020) Distinct Laminar Requirements for NMDA Receptors in Experience-Dependent Visual Cortical Plasticity. Cerebral Cortex. 30(4): 2555-2572. *Co-corresponding authors. DOI: 10.1093/cercor/bhz260.
Cooke SF, Komorowski RW, Kaplan ES, Gavornik JP, Bear MF (2015) Visual Recognition Memory, Manifest as Long-Term Habituation, Requires Synaptic Plasticity in V1. Nature Neuroscience. 18(2):262-71. DOI: 10.1038/nn.3920