Spacing theta-burst stimulation enhances synaptic potentiation in the vulnerable prefrontal cortex

Neuromodulation with intermittent theta-burst stimulation (iTBS) is a clinical treatment for major depression. One postulated mechanism of iTBS is to strengthen the synaptic connections which activate the prefrontal cortex to regulate mood. With ex vivo electrical stimulation and neuronal calcium imaging, we demonstrate that a common, clinical iTBS pattern (600-stimuli, ∼3-min) reliably strengthens the synaptic recruitment of the adult mouse prefrontal cortex. This synaptic potentiation, however, becomes less reliable in the depressive-like mouse model of prolonged social isolation. Examining the complex calcium elevations during clinical iTBS reveals that the induction peaks rise higher in social isolation but no longer predict the synaptic potentiation outcome. To better regulate calcium dynamics during induction, we test a paradigm with fewer iTBS episodes, separated by longer intervals. This spaced iTBS (90-stimuli, ∼10-min) in the adult prefrontal cortex limits calcium elevation during induction and yields greater long-term potentiation (LTP) following either juvenile-or adult-onset social isolation. This research illustrates new strategies to interrogate and to enhance synaptic plasticity in the vulnerable prefrontal cortex.