Abstract
Bipolar disorder is a chronic and debilitating neuropsychiatric illness characterised by emotional lability, and no primary cause has yet been identified. For over 100 years, lithium has been a first-line therapeutic agent in treating bipolar disorder, but its mechanism of action also remains unclear.
Other treatments for mood disorders include antiepileptics and antipsychotics, but treatment remains a challenge, and many patients do not respond well. The lack of objective screening tools presents a major challenge to the treatment and diagnostic process.
Lithium's efficacy is currently considered to derive from mechanisms involving intracellular signalling and neuronal functioning, but we remain broadly ignorant of the nature and cellular location of the therapeutic effect, in particular, whether any effect derives from modulation of the action potential on the axon rather than the neuronal cell body.Changes in the axonal action potential waveform following activity provide short-term axonal plasticity in which synaptic efficacy and the synchrony of neural networks can be altered. Additionally, axonal integrity and myelination are frequently reported to be disrupted in bipolar disorder patients. Despite the importance of the action potential waveform in determining neural functioning, particularly during communication between brain regions, the electrophysiological effects of treatments used in bipolar disorder on axon conduction remain poorly understood.
This is partly due to limited investigative techniques and brain slice preparations available for electrophysiological investigations of central axons.
Therefore, I aimed to develop a novel ex vivo axonal preparation to investigate the mechanism of action of lithium and antiepileptic drugs using the mouse lateral olfactory tract. I hypothesised that some of the therapeutic benefits of lithium and antiepileptic drugs (carbamazepine, lamotrigine, valproate) might derive from modulation of the axonal action potential waveform.
I measured the change in the compound action potential depolarisation and repolarisation amplitudes, duration and conduction velocity following stimulation with a 10Hz tetanic or bursting protocol. The effects of 4-aminopyridine on the axonal action potential of the lateral olfactory tract identified it as a potential lithium-like alternative therapeutic and investigated.
Results from the ex vivo preparation showed that lithium impacted action potential parameters to a greater extent following stimulation at 1Hz than at 10Hz, suggesting an activity-dependent effect on axonal action potential broadening. Carbamazepine, lamotrigine and lithium all reduced conduction velocity following 10 minutes of 10Hz stimulation. Lithium, lamotrigine and 4-aminopyridine decreased depolarisation and repolarisation amplitudes following 10Hz tetanic stimulation. In both the tetanic and bursting protocols, 4-aminopyridine increased the duration of the repolarisation and depolarisation phase, and in the bursting protocol, carbamazepine also increased the depolarisation duration.
In the presence of lamotrigine and carbamazepine, lithium’s effects on the action potential waveform were significantly enhanced. However, in the presence of 4-aminopyridine, most of lithium's effects on the action potential waveform were occluded, suggesting a shared axonal target.
These results were translated into a clinical trial investigating the effects of lithium and 4-aminopyridine on EEG activity profiles of healthy volunteers. Lithium increased EEG connectivity in a frequency range similar to the ex vivo findings (1-8Hz) within regions of the default mode, salience and central executive networks.
These results suggest that axonal ion channel modulation with lithium and antiepileptics may treat BD, at least in part, by altering axonal action potential conduction. By restoring signal conduction down compromised axons, modulation of the axonal action potential may provide a means to restore connectivity within and between regions of the brain implicated in bipolar disorder such as emotional and cognitive networks. Therefore, novel therapeutics targeting axonal action potential conduction may provide a means to treat bipolar disorder. Axonal conduction can also be reflected by changes in EEG, suggesting a diagnostic or treatment response biomarker may be detected in it.