Abstract
Bipolar disorder (BD) is a chronic neuropsychiatric illness characterised by episodes of mania and depression, with no consensus on its neuropathology or clear drug targets. Axon-myelin interactions are implicated in BD, evidenced by genetic studies showing alterations in myelin-related proteins and neuroimaging studies indicating white matter abnormalities in brain regions associated with cognitive and emotional processing.
To investigate the role of axons in the pathophysiology of BD, we developed a novel ex vivo axonal preparation of the mouse lateral olfactory tract (LOT). We recorded action potentials (AP) at two sites along the LOT, to examine the effects of 3 BD drug treatments (5mM lithium, 100µM carbamazepine, and 100µM lamotrigine) as well as a potential novel therapeutic (4µM 4-aminopyridine) on the compound AP of the LOT (n = 7-8 preparations per group). We quantified changes in AP amplitude, duration, and conduction velocity following a train of stimuli in both the presence and absence of these drugs.
Results revealed that all 4 drugs altered at least one AP waveform parameter by decreasing depolarisation/repolarisation amplitude or duration or reducing conduction velocity, consistent with the normal amplification of AP adaptation following trains of stimuli. Lithium had an activity-dependent effect, impacting AP amplitude and conduction velocity to a greater degree following 1Hz than 10Hz stimulation. The effects of lithium on the axonal AP were also enhanced in the presence of lamotrigine, carbamazepine, or 4-aminopyridine.
These findings suggest that modulating the axonal AP with lithium and antiepileptics may treat BD by restoring signal conduction where myelin is compromised. Additionally, the efficacy of combination therapy with lithium and antiepileptics in BD might result from synergistic modulation of the axonal AP, leading to enhanced activity effects on synaptic strength within neural networks.