Increase in Cortical Pyramidal Cell Excitability Accompanies Depression-Like Behavior in Mice: A Transcranial Magnetic Stimulation Study

Abstract

Clinical evidence suggests that cortical excitability is increased in depressives. We investigated its cellular basis in a mouse model of depression. In a modified version of forced swimming (FS), mice were initially forced to swim for 5 consecutive days and then were treated daily with repetitive transcranial magnetic stimulation (rTMS) or sham treatment for the following 4 weeks without swimming. On day 2 through day 5, the mice manifested depression-like behaviors. The next and last FS was performed 4 weeks later, which revealed a 4 week maintenance of depression-like behavior in the sham mice. In slices from the sham controls, excitability in cingulate cortex pyramidal cells was elevated in terms of membrane potential and frequencies of spikes evoked by current injection. Depolarized resting potential was shown to depend on suppression of large conductance calcium-activated potassium (BK) channels. This BK channel suppression was confirmed by measuring spike width, which depends on BK channels. Chronic rTMS treatment during the 4 week period significantly reduced the depression-like behavior. In slices obtained from the rTMS mice, normal excitability and BK channel activity were recovered. Expression of a scaffold protein Homer1a was reduced by the FS and reversed by rTMS in the cingulate cortex. Similar recovery in the same behavioral, electrophysiological, and biochemical features was observed after chronic imipramine treatment. The present study demonstrated that manifestation and disappearance of depression-like behavior are in parallel with increase and decrease in cortical neuronal excitability in mice and suggested that regulation of BK channels by Homer1a is involved in this parallelism.

Signaling pathways regulating Homer1a expression: implications for antidepressant therapy

“…The potential involvement of Homer1a in depression-like behavior has been suggested in several reports Szumlinski et al, 2005Szumlinski et al, , 2006Kato, 2009;Rietschel et al, 2010;Sun et al, 2011). Collectively, the data on Homer1 suggest distinct roles for both isoforms: Homer1a and Homer1b/c in behavioral response to stress.…”

“…Interestingly, specific siRNA knockdown of Homer1a in mPFC enhances depressive-like behavior and prevented the antidepressant effects of SD, imipramine and ketamine treatment, while viral overexpression of Homer1a in this region promotes antidepressant effects, demonstrating that Homer1a expression specifically in the mPFC is inversely correlated to the depressive-like behavior (Serchov et al, 2015a). In addition, non-pharmacological treatments of depression, like ECT and transcranial magnetic stimulation, a less invasive non-pharmacological antidepressant treatment, alternative to ECT, also upregulate Homer1a expression levels in the cortex (Sakagami et al, 2005;Conti et al, 2007;Sun et al, 2011). Indeed, Homer1a was proposed to be instrumental for the therapeutic effect of ECT in depression (Sakagami et al, 2005;Kato, 2009).…”

“…Several lines of evidence show that chronic treatment with classical antidepressants, like imipramine and fluoxetine upregulate Homer1a expression (Conti et al, 2007;Sun et al, 2011;Serchov et al, 2015a). The fact that these drugs require at least 2 weeks to increase Homer1a suggests for indirect mechanism of regulation (Serchov et al, 2015a).…”

Improvement of spatial learning by facilitating large-conductance calcium-activated potassium channel with transcranial magnetic stimulation in Alzheimer's disease model mice

“…However, neurobiological grounds of TMS effects have been studied largely in the context of antidepressant treatment by using animal models (Fleischmann et al, 1995;Zyss et al, 1997;Müller et al, 2000;Keck et al, 2001;Ikeda et al, 2005;Kim et al, 2006;Sun et al, 2011). By contrast, neurobiological evidence that might support a therapeutic application of TMS to AD is lacking.…”

Thermal and Mechanical Analysis of Novel Transcranial Magnetic Stimulation Coil for Mice

“…The efficacy of TMS cannot be appropriately assessed without generating consistent and reproducible electric and magnetic field profiles. Current methods for restraint include manually holding a mouse both with [13] and without addition restraining tools, such as placing the mouse a transparent cylinder where it is still relatively free to move [14]. Furthermore, existing small animal coils are too large for testing on mice and consequently stimulate the entire body rather than part of the brain [15].…”