EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) ON BRAIN CORTEX PLASTICITY IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

We recently reported that transcranial direct current stimulation (tDCS) enhances synaptic plasticity in several brain cortex areas along with modulating expression and/or phosphorylation of plasticity-related proteins including synaptophysin, CREB, CBP and BDNF (Podda et al., 2016; Paciello et al., 2018; Cocco et al., 2018). Here, we asked whether tDCS may unmask brain plasticity deficits before the appearance of over clinical signs of Alzheimer's disease (AD). We used the 3×Tg-AD mouse model developing a well characterized, time-dependent AD-like phenotype. We focused on 3-month-old 3×Tg-AD mice that do not exhibit any electrophysiological or behavioral alterations and are therefore reminiscent of preclinical AD. We compared their response with those of age-matched C57BL/6 mice exhibiting significant brain plasticity enhancement following tDCS. In these animals we studied the effects of anodal tDCS on: i) long-term potentiation (LTP) at CA3-CA1 synapses; ii) hippocampal-dependent learning and memory by Novel Object Recognition (NOR) and Morris Water Maze (MWM) tests; iii) expression and/or phosphorylation of synaptic proteins by Western blotting. We found that, differently from C57BL/6 mice, tDCS failed to significantly affect brain plasticity in 3-month-old 3×Tg-AD mice. In particular, LTP magnitude (60.4±7.1% vs. 55.1±6.8%; p=0.6) as well as memory assessed by NOR (preference index: 64.6±4.3% vs. 61.3±1.7%; p=0.6) and MWM tests (time spent in the target quadrant: 20.9±5.6% vs. 21.6±2.4%; p=0.9) were not significantly different in 3×Tg-AD mice subjected to either tDCS or sham stimulation. At molecular level, pCaMKII and pCREB were also not modulated by tDCS (p=0.5 and p=0.8, respectively) differently from what observed in age-matched C57BL/6 mice. Our findings suggest that in the 3×Tg-AD mouse model early plasticity deficits prevent tDCS to modulate LTP and memory before the AD-like phenotype is manifested. These findings pave the way to using tDCS as a potential diagnostic tool to detect early synaptic dysfunction in AD. This work was supported by the Italian Ministry of Health (RF-2013-02356444).