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Astrocyte reductions linked to major depression

Frontiers in Psychiatry
Reuters Health - 12/02/2021 - In the brains of severely depressed individuals, astrocytes immunoreactive to vimentin (VIM-IR) are decreased, further implicating astrocyte dysfunction in depression and suicide, researchers say.

Previous studies have shown decreased levels of astrocytes immunoreactive to glial fibrillary acidic protein (GFAP) in depression, as well.

"This study strengthens the theoretical rationale for trying to develop a drug that increases the number of astrocytes in the brain, to correct for the apparent loss of astrocytes in depression," Dr. Naguib Mechawar of McGill University in Montreal told Reuters Health by email. "These cells express unique proteins and receptors and have a considerable impact on brain function."

"Currently, no antidepressant has been developed to specifically target astrocytes, and so the feasibility and potential downsides are unknown."

That said, he added, "We can no longer consider major depressive disorder as an exclusively neuronal condition. We and others have observed a strong and consistent loss of astrocytes and astrocyte proteins in many brain regions, so these cells should definitely be taken into account when developing new pharmacological treatments."

Postmortem studies have implicated GFAP-IR astrocytes in the etiopathology of depression and suicide, but whether subpopulations of astrocytes are similarly affected was not clear, the authors note in Frontiers in Psychiatry.

Because VIM-IR and GFAP-IR astrocytes have different regional densities in the healthy brain, Dr. Mechawar and colleagues speculated they might also be differently altered in depression and suicide.

To investigate, they compared the densities of GFAP-IR and VIM-IR astrocytes in three brain regions - dorsomedial prefrontal cortex, dorsal caudate nucleus and mediodorsal thalamus. Samples came from 10 depressed adult White men (mean age, about 40) who committed suicide and 10 matched non-psychiatric controls who died suddenly in accidents.

Both GFAP-IR and VIM-IR astrocyte densities were globally reduced in depressed suicides relative to controls, although cell morphology was unaffected.

Given the close association between astrocytes and blood vessels, the team also assessed CD31-IR blood vessel densities in the same brain regions. CD31-IR blood vessel density and VIM-IR astrocyte morphometric features were similar in both groups, except in prefrontal white matter, where vascularization was increased and astrocytes displayed fewer primary processes in samples from the depressed group.

Summing up, the authors write, "We performed the first cross-regional assessment of astrocyte density and morphometry using two distinct astrocytic markers, as well as of vascular density in postmortem brain samples from depressed individuals and matched controls. We found a significant and widespread reduction in astrocyte densities (but no significant change in cell morphology) in depressed suicides relative to controls. Blood vessel density was only different (increased) in prefrontal cortex white matter of depressed suicides."

Dr. Eric Nestler, Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai in New York City and Chair of the Depression Task Force of the Hope for Depression Research Foundation, told Reuters Health by email, "This study reveals a widespread alteration of cerebral astrocytes in depression and suicide."

"Prior work has reported decreased numbers of astrocytes in the brains of humans with depression examined postmortem," he said. However, while those studies used GFAP, considered a standard astrocyte marker, "the present study is the first to look more deeply into this phenomenon by examining...vimentin."

"The present findings are an important lead and set up future studies to examine astrocyte changes in depression in far greater detail than ever accomplished before," he continued. "Most importantly: How does a decrease in vimentin+ astrocytes change brain function? Does the decrease represent a pathological change that contributes to depression's etiology and pathophysiology, or does it represent an adaptive change that attempts to limit abnormalities in the depressed brain caused by other factors?"

"We have known for some time that the brain contains more astrocytes than neurons. Moreover, the ratio of astrocytes to neurons increases through evolution, with a ratio of ~1.4:1 in human brain, ~0.4:1 in rodent brain, and ~0.2:1 in worms," he said. "This tells us that astrocytes are serving essential functions and indeed have been increasingly implicated in brain function both under normal conditions and in pathological states such as depression and many others."

"Future work will be needed to determine whether reduced numbers of astrocytes predominate in a subtype of depression--which one day might be discerned through brain imaging approaches and then guide treatments targeted to this abnormality," Dr. Nestler concluded.

SOURCE: https://bit.ly/3d8KSxx Frontiers in Psychiatry, online February 4, 2021.

By Marilynn Larkin

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