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The effects of cannabinoids on pre- and post-synaptic activity during learning

Primary Supervisor: Professor Nick Hartell, Department of Neuroscience, Psychology and Behaviour

Secondary Supervisor: Dr Martine Hamann

PhD project title: The effects of cannabinoids on pre- and post-synaptic activity during learning

University of Registration: University of Leicester

Project outline:

General Background.

Learning and adaptation of behaviour requires long-term changes in the strength of synaptic transmission that in turn lead to alterations in the patterns of neuronal firing. Using a novel transgenic mouse (SyG37) that expresses a genetically encoded calcium sensor in presynaptic terminals (Al-Osta et al., 2018), we have found that during aging, the ability of mice to learn tasks requiring the hippocampus diminishes and that this is accompanied by a change in synaptic properties. Synaptic responses to electrical stimulation are strengthened, the probability of transmitter release is increased and the level of calcium in presynaptic terminals is elevated both at rest and during synaptic activation (Pereda et al., 2019). In a parallel study, we have found that activation of the cannabinoid receptor (CB1R) lowers presynaptic calcium and reduces synaptic transmission at the same hippocampal synapses. Chronic treatment of aged mice with an endocannabinoid reverses some of the cognitive deficits associated with aging (Bilkei-Gorzo et al., 2017).

Objectives and Methods

In this project, we will combine state of the art imaging technology with genetically encoded fluorescent sensors and electrophysiology to examine pre- and post-synaptic changes in synaptic transmission within the hippocampus. We will establish how activation of the endocannabinoid system leads to changes in presynaptic properties and then how these presynaptic changes influence post-synaptic properties. To do this, we will first use SyG37 mice to characterise the mechanisms by which CBR1 activation changes presynaptic calcium signalling and synaptic transmission. We will then use miniature microscopes in concert with genetically encoded calcium and/or voltage indicators to examine neuronal activity in freely moving mice and see how pharmacological manipulation of the CB1R pathway leads to changes in neuronal activity and changes in the ability of mice to learn behavioural tasks involving hippocampal processing. Depending on the outcome of these results, and if time permits, we will examine whether cannabinoids can reverse changes in neuronal activity and cognition as a result of normal aging.


  1. Al-Osta I, Mucha M, Pereda D, Piqué-Gili M, Okorocha AE, Thomas R, Hartell NA (2018) Imaging Calcium in Hippocampal Presynaptic Terminals With a Ratiometric Calcium Sensor in a Novel Transgenic Mouse. Frontiers in cellular neuroscience 12:209.
  2. Bilkei-Gorzo A, Albayram O, Draffehn A, Michel K, Piyanova A, Oppenheimer H, Dvir-Ginzberg M, Racz I, Ulas T, Imbeault S, Bab I, Schultze JL, Zimmer A (2017) A chronic low dose of Delta9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med 23:782-787.
  3. Pereda D, Al-Osta I, Okorocha AE, Easton A, Hartell NA (2019) Changes in presynaptic calcium signalling accompany age-related deficits in hippocampal LTP and cognitive impairment. Aging cell:e13008.

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

    Techniques that will be undertaken during the project:

    Techniques that will be undertaken involve in vitro imaging of brain slices using standard fluorescent and multiphoton microscopes combined with electrophysiology. Some of the work will involve behaviour in awake mice and this will require training in animal handling, surgical techniques for viral expression of genetically modified sensors and lens implantation. A range of analysis techniques will be undertaken.

    Contact: Professor Nick Hartell, University of Leicester