SYNAPTIC PLASTICITY IN THE INJURED BRAIN DEPENDS ON THE TEMPORAL PATTERN OF STIMULATION.

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction, however little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency of neurostimulation in the normal cerebral cortex and after mild traumatic brain injury (mTBI), to inform therapies to strengthen or weaken neural circuits in injured brains, as well as to better understand the role of these factors in normal brain plasticity. Whole-cell (WC) patch-clamp recordings of evoked postsynaptic potentials (PSPs) in individual neurons, as well as field potential (FP) recordings, were made from layer 2/3 of visual cortex in response to stimulation of layer 4, in acute slices from control (naïve), sham operated, and mTBI rats. We compared synaptic plasticity induced by different stimulation protocols, 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). At the individual neuron level, dramatic differences in plasticity outcome occurred when the highly irregular stimulation protocol was used at 1 Hz or 10 Hz, producing an overall LTD in controls and shams, but a robust overall LTP after mTBI. Consistent with the individual neuron results, the plasticity outcomes for simultaneous FP recordings were similar, indicative of our results generalizing to a larger scale synaptic network than can be sampled by individual WC recordings alone. In addition to the differences in plasticity outcome between control (naïve or sham) and injured brains, the dynamics of the changes in synaptic responses that developed during stimulation were predictive of the final plasticity outcome. Our results demonstrate that the temporal pattern of stimulation plays a role in the polarity and magnitude of synaptic plasticity induced in the cerebral cortex while highlighting differences between normal and injured brain responses. Moreover, these results may be useful for optimization of neurostimulation therapies to treat mTBI and other brain disorders, in addition to providing new insights into downstream plasticity signaling mechanisms in the normal brain.

Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition.

The double-stranded RNA-activated protein kinase (PKR) was originally identified as a sensor of virus infection, but its function in the brain remains unknown. Here, we report that the lack of PKR enhances learning and memory in several behavioral tasks while increasing network excitability. In addition, loss of PKR increases the late phase of long-lasting synaptic potentiation (L-LTP) in hippocampal slices. These effects are caused by an interferon-γ (IFN-γ)-mediated selective reduction in GABAergic synaptic action. Together, our results reveal that PKR finely tunes the network activity that must be maintained while storing a given episode during learning. Because PKR activity is altered in several neurological disorders, this kinase presents a promising new target for the treatment of cognitive dysfunction. As a first step in this direction, we show that a selective PKR inhibitor replicates the Pkr(-/-) phenotype in WT mice, enhancing long-term memory storage and L-LTP.

The kinetic profile of intracellular calcium predicts long-term potentiation and long-term depression.

Efficiency of synaptic transmission within the neocortex is regulated throughout life by experience and activity. Periods of correlated or uncorrelated presynaptic and postsynaptic activity lead to enduring changes in synaptic efficiency [long-term potentiation (LTP) and long-term depression (LTD), respectively]. The initial plasticity triggering event is thought to be a precipitous rise in postsynaptic intracellular calcium, with higher levels inducing LTP and more moderate levels inducing LTD. We used a pairing protocol in visual cortical brain slices from young guinea pigs with whole-cell recording and calcium imaging to compare the kinetic profiles of calcium signals generated in response to individual pairings along with the cumulative calcium wave and plasticity outcome. The identical pairing protocol applied to layer 2/3 pyramidal neurons results in different plasticity outcomes between cells. These differences are not attributable to variations in the conditioning protocol, cellular properties, inter-animal variability, animal age, differences in spike timing between the synaptic response and spikes, washout of plasticity factors, recruitment of inhibition, or activation of different afferents. The different plasticity outcomes are reliably predicted by individual intracellular calcium transients in the dendrites after the first few pairings. In addition to the differences in the individual calcium transients, the cumulative calcium wave that spreads to the soma also has a different profile for cells that undergo LTP versus LTD. We conclude that there are biological differences between like-type cells in the dendritic calcium signals generated by coincident synaptic input and spiking that determine the sign of the plasticity response after brief associations.