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

Abstract

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-minutes) 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. To better understand this change, we examine the impact of social isolation on the complex pattern of calcium elevation during clinical iTBS. In social isolation, the calcium peaks rise more prominently, but the induction peak no longer predicts 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-minutes) in the adult prefrontal cortex limits calcium elevation during induction and yields reliable 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. Significance Statement Neuromodulation therapy in major depression aims to boost synaptic potentiation in the prefrontal cortex. Since this region lacks simple behavioral readouts, preclinical studies using rodent brain slices are valuable to test and refine stimulus patterns. Here, we demonstrate that ex vivo neuronal calcium imaging reliably captures the strength and spatial spread of synaptic plasticity in the mouse prefrontal cortex in response to a common, clinical protocol (intermittent theta-burst stimulation, iTBS). This approach is sufficiently sensitive to detect problems in synaptic potentiation associated with social isolation and to identify translationally relevant changes to improve prefrontal plasticity in the vulnerable brain.