RESTORING SYNAPTIC PLASTICITY IN THE DEMYELINATED BRAIN: THE THERAPEUTIC EFFICACY OF FOCUSED ULTRASOUND IN THE HIPPOCAMPUS

Chronic demyelination leads to significant disruptions in neural circuit connectivity and synaptic plasticity, likely contributing to the cognitive dysregulation observed in multiple sclerosis. While low-intensity focused ultrasound stimulation (LIFUS) is recognized for its neuromodulatory potential, its ability to rescue functional deficits in demyelinated circuits remains to be fully explored. We investigated whether specific LIFUS protocols could restore hippocampal long-term potentiation (LTP) and neuronal excitability, viability, and synaptic efficacy in a rodent model of demyelination. Male and female C57BL/6 mice were fed a 0.2% cuprizone diet for six weeks. Demyelination was confirmed via histological analysis of the corpus callosum. We then applied LIFUS characterized by a 1 MHz fundamental frequency, a 5 Hz pulse repetition frequency (PRF), a 30% duty cycle, and an intensity of approximately 1.3 W/cm². Functional recovery was assessed using ex vivo field excitatory postsynaptic potential (fEPSP) recordings in acute hippocampal slices. We utilized input-output (I/O) curves and high-frequency stimulation (HFS) to evaluate basal transmission and LTP, respectively. We hypothesise that Cuprizone-treated mice exhibit a marked reduction in I/O slope and a failure to sustain LTP compared to controls. Implementation of the LIFUS will yield a measurable recovery of synaptic excitability and rescue any deficits observed via a significant enhancement in post-HFS potentiation in LIFUS-treated slices. These results will demonstrate that LIFUs at 1.3 W/cm² can effectively modulate hippocampal circuitry to overcome plasticity deficits induced by cuprizone. This suggests that ultrasound-based neuromodulation may serve as a potent non-invasive therapeutic for restoring functional integrity in demyelinating diseases.