Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [11C]PBR28 PET study

The cognitive repercussions of alcohol dependence are well documented. However, the literature remains somewhat ambiguous with respect to which distinct cognitive functions are more susceptible to impairment in alcoholism and to how duration of abstinence affects cognitive recovery. Some theories claim alcohol negatively affects specific cognitive functions, while others assert that deficits are more diffuse in nature. This is the first meta-analysis to examine cognition in alcohol abuse/dependence and the duration of abstinence necessary to achieve cognitive recovery. A literature search yielded 62 studies that assessed cognitive dysfunction among alcoholics. Effect size estimates were calculated using the Comprehensive Meta-Analysis V2, for the following 12 cognitive domains: intelligence quotient, verbal fluency/language, speed of processing, working memory, attention, problem solving/executive functions, inhibition/impulsivity, verbal learning, verbal memory, visual learning, visual memory and visuospatial abilities. Within these 12 domains, three effect size estimates were calculated based on abstinence duration. The three groups were partitioned into short- ( 1 year) term abstinence. Findings revealed moderate impairment across 11 cognitive domains during short-term abstinence, with moderate impairment across 10 domains during intermediate term abstinence. Small effect size estimates were found for long-term abstinence. These results suggest significant impairment across multiple cognitive functions remains stable during the first year of abstinence from alcohol. Generally, dysfunction abates by 1 year of sobriety. These findings support the diffuse brain hypothesis and suggest that cognitive dysfunction may linger for up to an average of 1 year post-detoxification from alcohol. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPO radioligands, [(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2-[(18)F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide] and [(11)C]SSR180575 (7-chloro-N,N-dimethyl-5-[(11)C]methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), showed a significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.

Purpose Microglia represent the primary resident immune cells in the CNS, and have been implicated in the pathology of neurodegenerative diseases. Under basal or “resting” conditions, microglia possess ramified morphologies and exhibit dynamic surveying movements in their processes. Despite the prominence of this phenomenon, the function and regulation of microglial morphology and dynamic behavior are incompletely understood. We investigate here whether and how neurotransmission regulates “resting” microglial morphology and behavior. Methods We employed an ex vivo mouse retinal explant system in which endogenous neurotransmission and dynamic microglial behavior are present. We utilized live-cell time-lapse confocal imaging to study the morphology and behavior of GFP-labeled retinal microglia in response to neurotransmitter agonists and antagonists. Patch clamp electrophysiology and immunohistochemical localization of glutamate receptors were also used to investigate direct-versus-indirect effects of neurotransmission by microglia. Results Retinal microglial morphology and dynamic behavior were not cell-autonomously regulated but are instead modulated by endogenous neurotransmission. Morphological parameters and process motility were differentially regulated by different modes of neurotransmission and were increased by ionotropic glutamatergic neurotransmission and decreased by ionotropic GABAergic neurotransmission. These neurotransmitter influences on retinal microglia were however unlikely to be directly mediated; local applications of neurotransmitters were unable to elicit electrical responses on microglia patch-clamp recordings and ionotropic glutamatergic receptors were not located on microglial cell bodies or processes by immunofluorescent labeling. Instead, these influences were mediated indirectly via extracellular ATP, released in response to glutamatergic neurotransmission through probenecid-sensitive pannexin hemichannels. Conclusions Our results demonstrate that neurotransmission plays an endogenous role in regulating the morphology and behavior of “resting” microglia in the retina. These findings illustrate a mode of constitutive signaling between the neural and immune compartments of the CNS through which immune cells may be regulated in concert with levels of neural activity.