Page - (000179) - in Biomedical Chemistry: Current Trends and Developments

impairing diseases, such as Alzheimer’s disease (AD), where a profound alteration in the density of serotonergic receptors was shown, the action of serotonin seems to rely on the interplay with other neurotransmitters and second messengers relevant to memory formation. 2.4.2 Glutamate Neurotransmission and Cognition Glutamate is a ubiquitous anionic amino acid that exists in all cell types, but in the brain it acts as a signaling molecule, being stored and released from the glutamatergic neurons subpopulation. Glutamate is considered the main excitatory neurotransmitter in the CNS, used by around half of the neurons in the brain (Fonnum, 1984; Liguz-Lecznar, 2007). Glutamate is derived from glutamine through enzymatic conversion involving phosphate-activated glutaminase (PAG) (Albrecht, 2007), and is stored in small synaptic vesicles at nerve terminals by the action of vesicular glutamate transporters 1 and 2 (VGLUT1 and 2). Following membrane depolarization and Ca2+ entry into cells, synaptic vesicles fuse with the plasma membrane and release the glutamate by exocytosis into the synaptic cleft. After being released, glutamate is transported back to the neuron or into the glial cells by the action of excitatory amino acid transporters (EAATs). In astrocytes, glutamate is converted to glutamine by glutamine synthase, and glutamine is transferred back to neurons, probably through the sequential action of amino acid system N and A transporters (Albrecht, 2007; Liguz-Lecznar, 2007; Lee, 2010). Once released from the presynaptic nerve terminal, glutamate binds to specific receptors in the postsynaptic membrane to conduct excitatory transmission. Pre-synaptic glutamate receptors act in the modulation of glutamate release. The effects of glutamate are mediated by activation of ionotropic or metabotropic receptors, which differ in their molecular, biochemical, physiological and pharmacological properties (Kew, 2005; Kim, 2001). The ionotropic glutamate receptors have been classified into three distinct subgroups, α.amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA), N-methyl- Daspartate (NMDA) and Kainate (KA) receptors (Dingledine, 1999; Mayer, 2004). AMPA and kainate receptors are responsible for most of the fast excitatory transmission in the vertebrate CNS. They are voltage-