Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_205_библиотеки_им_акад_М_И_Перельмана

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In humans, 80% of neocortical neurons are excitatory and form 85% of synapses, whereas 20% of neocortical neurons are inhibitory and form 15% of synapses (Doug las and Martin 2007). Excitatory neurons use glutamate as the main excitatory neuro­transmitter, sending excitatory signals within and across brain regions (Orrego and Villanueva 1993). Activity of these excitatory neurons is modulated by inhibitory in terneurons that use GABA as their main neurotransmitter (DeFelipe et al. 2013; Fino et al. 2013). Postmortem studies of subjects with MDD or bipolar disorder found higher glutamate levels in the frontal cortex, suggesting that excitatory glutamatergic function is elevated in this brain region in both disorders (Hashimoto et al. 2007; Lan et al. 2009). In the OFC of subjects with MDD, lower levels of excitatory amino acid transporters 1 and 2, which are expressed in astrocytes and are responsible for recy cling synaptic glutamate, were reported; lower expression of these transporters is consistent with higher levels of glutamate in subjects with MDD (Miguel-Hidalgo et al. 2010). Altered expressions of glutamate receptor genes and of genes related to glu­tamate recycling were reported in several cortical brain regions and in the amygdala of subjects with MDD who died from suicide (Sequeira et al. 2009), suggesting gluta matergic dysfunction in mood disorders. Evidence also suggests that some of these changes in glutamate-related genes might be sex specific in the DLPFC, with higher expression in females, but not in males, with MDD (Gray et al. 2015).

Several studies have also reported inhibitory GABA-related alterations in mood disorders. Subjects with MDD exhibited lower GABA concentrations in postmortem cortical brain tissue, suggesting that inhibitory GABAergic function is lower in the cortex of subjects with MDD (Honig et al. 1988). In line with findings of lower GABA

concentrations in MDD, lower expression of glutamic acid decarboxylase 67 (GAD67), a GABA-synthesizing enzyme, was reported in the DLPFC of medication-free subjects with MDD (Karolewicz et al. 2010). Interestingly, results from this study also sug gested that antidepressant medication normalizes GAD67 levels (Karolewicz et al.

Canonical cortical microcircuits are composed of excitatory pyramidal cells that are innervated by various inhibitory GABA GABA neuron subtypes perform different tasks in cortical microcircuits. We consider two GABA neuron subtypes here: those that express the calcium-binding protein parvalbumin and those that express the neuropeptide somatostatin. GABA interneu­rons that express parvalbumin receive inhibitory input from other parvalbumin cells and excitatory input from pyramidal cells, and innervate the perisomatic region of pyramidal cells, thereby regulating excitatory signal output (reviewed in Wamsley and Fishell 2017). Somatostatin-expressing GABA interneurons, which often coex­press the calcium-binding protein calbindin and may also contain the neuropeptides Y and/or cortistatin, innervate the distal dendrites of excitatory pyramidal cells (Fino et al. 2013; Packer et al. 2013). Notably, the same canonical microcircuits exist in the basolateral amygdala.

lower somatostatin, neuropeptide Y, cortistatin, and parvalbumin mRNA levels (Tripp et al. 2012); lower levels of neuropeptide Y and cortistatin are consistent with lower somatostatin, because these are often coexpressed in the same GABA interneu­rons. Reductions in somatostatin mRNA were observed across cortical layers in the subgenual cingulate (Seney et al. 2015). GABA-related deficits were also present in the basolateral amygdala complex, with lower levels of somatostatin, neuropeptide Y, and cortistatin mRNA, but not of parvalbumin mRNA, in female subjects with MDD (Guilloux et al. 2012); interestingly, these GABA-related deficits were not observed in the basolateral amygdala of male subjects with MDD, suggesting sex specificity for GABA deficits in the basolateral amygdala in subjects with MDD (Sibille et al. 2009). Further characterization of the somatostatin deficits in the basolateral amygdala com plex in female subjects with MDD showed a lower density of detectable somatostatin­positive neurons across several nuclei, with lower somatostatin mRNA per cell re­stricted to the basomedial nucleus (Douillard-Guilloux et al. 2017).