Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice

Abstract

Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnestic rats have demonstrated that DBS targeted to the fimbria-fornix1-3, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory3-5. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder (IDD). IDDs are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We hypothesized that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett Syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP26, RTT appears by the second year of life, causing profound impairment in cognitive, motor, and social skills along with an array of neurological features7; RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity8-11. Here we show that forniceal DBS in RTT mice rescued contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restored in vivo hippocampal long-term potentiation (LTP) and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT.

Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model

“…Finally, we explored the effects of deep brain stimulation (DBS) of the fornix on these phenotypes, since DBS normalizes hippocampus-dependent learning and memory in Rett mice (Hao et al, 2015). We therefore implanted 6- to 8-week old Rett mice and WT littermates with chronic stimulating electrodes targeted unilaterally to the fimbria-fornix under the guidance of evoked potential recordings in the hippocampus (Figure 4A).…”

“…We therefore implanted 6- to 8-week old Rett mice and WT littermates with chronic stimulating electrodes targeted unilaterally to the fimbria-fornix under the guidance of evoked potential recordings in the hippocampus (Figure 4A). Mice in the DBS group received daily DBS for 2 weeks (Hao et al, 2015), and mice in the sham group underwent identical procedures except for DBS. We performed experiments 3 weeks after the last stimulation session, matched to the time of behavioral rescue (Hao et al, 2015).…”

“…Mice in the DBS group received daily DBS for 2 weeks (Hao et al, 2015), and mice in the sham group underwent identical procedures except for DBS. We performed experiments 3 weeks after the last stimulation session, matched to the time of behavioral rescue (Hao et al, 2015). Chronic DBS but not sham-DBS normalized synchrony between CA1 pyramidal neurons to WT-like levels (Figure 4B) and restored the mutant circuit’s homeostatic responsiveness (Figures 4C and D).…”

Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model

“…Induction and recording of hippocampal synaptic plasticity in vivo were conducted as previously published with a few modifications (Davis et al, 1997; Hao et al, 2015; Tang and Dani, 2009). Mice were secured on a stereotaxic frame (David Kopf) with 1–2% isoflurane as anesthesia.…”

“…Since the latency of the population spike usually decreases following LTP induction, it is impractical to compare the initial slope of the fEPSP (field excitatory postsynaptic potential) before and after LTP induction in awake animals (Jones et al, 2001; Malleret et al, 2001). Accordingly, we quantified the amplitude of the population spikes (Hao et al, 2015; Tang and Dani, 2009). Data were averaged every 5 min and normalized to the baseline measured over the 10 min before tetanic stimulation and presented as mean ± standard error of mean.…”