Glial and glutamatergic markers in depression, alcoholism, and their comorbidity

Abstract

Background-Alteration of glutamatergic neurotransmission in the prefrontal cortex (PFC) may contribute to the pathophysiology of alcoholism and major depressive disorder (MDD). Among glial cells, astrocytes are mostly responsible for recycling synaptic glutamate by uptake through excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2), and conversion to glutamine with glutamine synthetase (GS). Low density of astrocytes in the PFC of "uncomplicated' alcoholics and MDD subjects may parallel altered glutamate transporters and GS in the PFC.Methods-Immunohistochemistry and Western blotting for glutamate transporters, GS and glial fibrillary acidic protein (GFAP) were applied to postmortem tissue of the left orbitofrontal cortex from 13 subjects with MDD, 13 with alcoholism, 10 with comorbid alcoholism plus MDD (MDA), and 13 non-psychiatric controls. Area fraction of immunoreactivity was measured in sections, and protein levels in Western blots.Results-EAAT2 immunoreactivity was significantly lower in MDD and MDA subjects than in controls. EAAT1 levels were lower in MDA and MDD subjects as compared to controls, while GS levels in MDA were significantly lower than in alcoholics and controls, and lower in MDD subjects than in alcoholics. Area fraction of GFAP was lower in MDD, but not in MDA subjects as compared to controls or alcoholics.Limitations-High variability of protein levels in some groups and effects of antidepressant treatment, although appearing to be limited, cannot be fully evaluated.Conclusions-There are differential changes in the expression of glial glutamatergic markers in depression and alcoholism, suggesting a depletion of certain aspects of glutamatergic processing in depression.

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder

“…Altered expression of glutamate transporter genes has been reported previously in a number of studies of neurodegenerative and psychiatric diseases, [32][33][34] including MDD. 20,35 The present study provides direct evidence of astrocyte pathology in the cell body region of a monoamine neurotransmitter, indicating that glia cell abnormalities reported in more superior/rostral brain regions in MDD 16,19 extend to the brainstem and may contribute to pathology of mono amine systems.…”

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…The most abundant glutamate transporter in the brain is EAAT2 (synonyms: GLT1 and SLC1A2) which is mainly expressed by astrocytes, making them a vital element of the defense against excitotoxicity (Fontana, 2015; Kim et al, 2011). Not surprisingly, loss or attenuation of glial glutamate transporters have been implicated in the pathogenesis of many CNS disorders, such as ALS (Rothstein, 2009), PD (Plaitakis and Shashidharan, 2000), stroke (Lai, Zhang, & Wang, 2014), epilepsy (Tanaka et al, 1997; Wetherington, Serrano, & Dingledine, 2008), HD (Arzberger, Krampfl, Leimgruber, & Weindl, 1997), AD (Jacob et al, 2007; Masliah, Alford, DeTeresa, Mallory, & Hansen, 1996), and major psychiatric disorders (Choudary et al, 2005; Lauriat and McInnes, 2007; Miguel‐Hidalgo et al, 2010). To the contrary, many animal studies indicate that upregulation of EAAT2 provides significant beneficial effects in models of disease (Harvey et al, 2011; Kong et al, 2012; Miller et al, 2012a; Takahashi et al, 2015b).…”

The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

“…Some studies suggest alcohol dependence is related to a hyper excitable state caused by excess extracellular glutamate [73]. Expression changes in astrocyte glutamate transporters are observed in alcoholics and alcohol-exposed rodents [74,75]. Upregulation of glutamate transporters in postmortem alcoholic brain could be a sign of compensation for increased levels of extracellular glutamate.…”