Fig. 4: Schematic representation of the potential molecular mechanisms contributing to LHb hyperactivity in preclinical models of depression and the clinical population.

DNA hypomethylation leads to an increased expression of glutamatergic excitatory genes. Greater ßCaMKII gene and subsequent protein expression then results in an increased surface expression of AMPAR. Together with increased NMDA subunit expression and p11 protein expression, these molecular changes potentiate glutamatergic signalling. GABAergic transmission is attenuated via reduced expression of GABAßR1/2 and increased activity of the PP2A enzyme which leads to GABA-GIRK complex internalisation. Increased expression of the endocannabinoid, 2-AG, acts via the CB1 receptor to inhibit GABA release. Greater expression of the Astrocytic Kir4.1 potassium transporter, reduces the resting membrane potential leading the neuron in a state more primed to fire and compromised BBB integrity leads to greater cytokine infiltration. A comparison of the a human and b rodent Hb and the respective boundaries of the MHb and LHb is shown in the bottom left. AMPA α-amino-3-hydroxy-5-methyl-4-isoxazoldpropionic acid, ßCaMKII ß calmodulin-dependent kinase II, BBB blood brain barrier, CB1 cannabinoid type 1 receptor, Glu glutamate, GABA gamma aminobutyric acid, Kir4.1 inward rectifying potassium 4.1 channel, LHb lateral habenula, MHb medial habenula, NMDA N-methyl-D-aspartate receptor, PP2A protein phosphatase 2A, VHb ventral habenula, 2-AG 2- arachidonoylglycerol.