Imbalance in excitation and inhibition in sgACC is associated with depression in dementia with Lewy bodies.

Depression in dementia with Lewy bodies (DLB) is a common neuropsychiatric symptom associated with reduced quality in life. Structural, functional and neurochemical abnormalities in glutamatergic and GABAergic neurotransmission are implicated in the pathophysiology of depression, showing changes in regions involved in emotional processing, including the subgenual cingulate cortex (sgACC), which shows pathological changes in DLB. Using post-mortem tissue from DLB patients and controls, we assessed synaptic and neurochemical changes within the sgACC in relation to depression in DLB. We identified a reduction of layer V GABAergic neurones in depressed DLB cases, potentially indicating reduced inhibition of layer V pyramidal neurons, leading to altered excitation. High-resolution confocal imaging demonstrated a significantly increased volume of presynaptic glutamatergic synapses containing phosphorylated α-synuclein (s129) in DLB cases, and specifically in depressed DLB cases, potentially as a compensatory response to the accumulation of pathological s129. GABAergic synapses containing s129 were enlarged in both DLB groups showing no depression specific changes. Selective reductions in glutamatergic and GABAergic receptors were seen in depressed DLB cases, suggesting a role in the pathophysiology of depression in DLB, that may prove amenable to therapy with fast-acting antidepressants. Interactions with serotonergic and dopaminergic innervation were observed, where preserved 5HT3B receptor and calbindin characterised non-depressed DLB patients. In depressed DLB cases, this may lead to reduced inhibition of lower layer pyramidal neurones due to reduced dopaminergic coupling and enhanced excitatory activity within the cingulate. Overall, our findings suggest altered excitatory and inhibitory neurotransmission may contribute to the development of depression in DLB.