Genetic inactivation of the vesicular glutamate transporter 2 (VGLUT2) in the mouse: What have we learnt about functional glutamatergic neurotransmission?

During the past decade, three proteins that possess the capability of packaging glutamate into presynaptic vesicles have been identified and characterized. These three vesicular glutamate transporters, VGLUT1–3, are encoded by solute carrier genes Slc17a6–8. VGLUT1 (Slc17a7) and VGLUT2 (Slc17a6) are expressed in glutamatergic neurons, while VGLUT3 (Slc17a8) is expressed in neurons classically defined by their use of another transmitter, such as acetylcholine and serotonin. As glutamate is both a ubiquitous amino acid and the most abundant neurotransmitter in the adult central nervous system, the discovery of the VGLUTs made it possible for the first time to identify and specifically target glutamatergic neurons. By molecular cloning techniques, different VGLUT isoforms have been genetically targeted in mice, creating models with alterations in their glutamatergic signalling. Glutamate signalling is essential for life, and its excitatory function is involved in almost every neuronal circuit. The importance of glutamatergic signalling was very obvious when studying full knockout models of both VGLUT1 and VGLUT2, none of which were compatible with normal life. While VGLUT1 full knockout mice die after weaning, VGLUT2 full knockout mice die immediately after birth. Many neurological diseases have been associated with altered glutamatergic signalling in different brain regions, which is why conditional knockout mice with abolished VGLUT-mediated signalling only in specific circuits may prove helpful in understanding molecular mechanisms behind such pathologies. We review the recent studies in which mouse genetics have been used to characterize the functional role of VGLUT2 in the central nervous system

Caffeine Consumption Prevents Diabetes-Induced Memory Impairment and Synaptotoxicity in the Hippocampus of NONcZNO10/LTJ Mice

Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A1 and A2A receptors) emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7–11 months when kept under an 11% fat diet. Caffeine (1 g/l) was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25), mainly glutamatergic (vesicular glutamate transporters), and increased astrogliosis (GFAP immunoreactivity) compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A2A receptors and down-regulated A1 receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes