The impact of early life adversity on synaptic plasticity and memory—a novel therapeutic approach

Adverse childhood experiences (ACEs) are increasingly recognised as key risk factors for several negative health outcomes in adulthood, including addiction, chronic pain, anxiety disorders, depression, and memory impairment, many of which are highly co-morbid. The neuroscience behind these outcomes has been studied in mouse models of early-life adversity (ELA), including the ‘limited bedding and nesting’ paradigm in which a reduced availability of nesting material during postnatal days 2-9 causes a fragmentation of maternal care. On reaching adulthood, mice that have undergone this procedure show cognitive deficits such as impaired spatial recognition memory and depression-like behaviours such as a reduced desire for social interaction. Our preliminary in-house data indicate that these mice also have impairments in long-term potentiation (LTP) of synaptic strength, a cellular analogue of the processes thought to underlie memory formation. Pharmacological treatments that can reverse these impairments might have therapeutic potential for treating some of the negative consequences of ELA. And drugs that can boost LTP might also offer benefits in other conditions in which memory is impaired, including neurodegenerative disorders such as Alzheimer’s Disease. An example of such a drug is tianeptine, an atypical antidepressant and cognitive enhancer, whose mechanism of action was poorly understood until recently. However, there is mounting evidence for the surprising possibility that tianeptine’s therapeutic actions stem from its activation of opioid receptors in brain areas such as the hippocampus that are involved in both memory and mood disorders. In support of this idea, our preliminary data indicate that tianeptine can enhance the transmission of information at hippocampal synapses, both by blocking inhibitory neurotransmission and enhancing excitatory transmission, via opioid-receptor-dependent mechanisms.

The current project will involve a further exploration of this topic, using a multi-level laboratory-research-based approach to investigate the impact of early-life adversity (ELA) on hippocampal function, and the therapeutic actions of tianeptine. First, the behavioural consequences of ELA on spatial memory in mice will be studied using a variety of behavioural tasks, and the ability of tianeptine to reverse ELA-induced impairments will be assessed. At the cellular level, the effects of both ELA and tianeptine administration on synaptic transmission and synaptic plasticity will be investigated in isolated hippocampal slices in vitro, focussing on the cellular mechanisms of tianeptine’s actions. Lastly, the effects of both ELA and tianeptine on gene and protein expression in multiple regions, including the hippocampus, will be assessed. By studying tianeptine’s novel mechanisms of action, the ultimate goal of this project is to identify novel avenues for therapeutic intervention when hippocampal function is compromised.

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