Synaptic Plasticity in the Injured Brain Depends on the Temporal Pattern of Stimulation

Abstract

Background. Neurostimulation is increasingly used as a therapeutic intervention. Alterations in strength of synaptic connections (plasticity: long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of synaptic conditioning. However, little is known about the contribution of the temporal pattern of synaptic activation to plasticity in normal or injured brains.Objective. We explore interactions of temporal pattern and frequency in normal cortex and after mild traumatic brain injury (mTBI) to understand the role of temporal pattern in healthy brains and inform therapies to strengthen or weaken circuits in injured brains.Methods. Whole-cell (WC) patch-clamp recordings of evoked postsynaptic potentials (PSPs) and field potentials (FPs) were made from layer 2/3, in response to stimulation of layer 4, in acute cortical slices from control (naive), sham, and mTBI rats. We compared plasticity induced by different stimulation paradigms, each consisting of a specific frequency (1 Hz, 10 Hz, or 100 Hz), continuity (continuous or discontinuous), and temporal pattern (perfectly regular, slightly irregular, or highly irregular).Results. Within each stimulation paradigm plasticity for individual cells was heterogeneous. Highly irregular stimulation produced net LTD in controls, but net LTP after mTBI (except for 100 Hz paradigms). The kinetic profile of responses during conditioning was predictive of plasticity outcome under some conditions. Simultaneous WC and FP recordings had highly correlated plasticity outcomes.Conclusions. These experiments demonstrate that temporal pattern contributes to induction of synaptic plasticity in the normal brain and that contribution is altered by mTBI in ways that may inform brain stimulation therapies.HighlightsEach temporal pattern of stimulation produced heterogeneous plasticity outcomesHighly irregular stimulation produced LTD in controls, but LTP after mild TBIThe kinetic profile of conditioning responses was predictive of plasticity outcomeWhole-cell and field potential measurements of plasticity were highly correlated