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Neuron 1995;15: -aminobutyric acid: a receptor blockade in the basolateral 1029–1039 oxcarbazepine 150mg lowest price. Excitatory amino acid receptors in the required for long-term but not short-term memory of extinction bsolateral amygdala regulate anxiety responses in the social inter- learning buy oxcarbazepine 600mg with visa. Amygdalar neuropep- a corticotroin-releasing factor antagonist into the central nucleus tide Y Y-1 receptors mediate the anxiolytic-like actions of neuro- of the amygdala reverses anxiogenic-like effects of ethanol with- peptide Y in the social interaction test cheap 150mg oxcarbazepine mastercard. N-methyl-D-aspartate lesions of the lat- central amygdalar nucleus during gastric stress ulcer formation eral and basolateral nuclei of the amygdala block fear-poten- in rats. TRH-enkephalin interactions in the amyg- 1992;106:72–80. Blockade of GABAA receptors in the Regul Pept 1991;35:11–17. Effects of intra-amygdalar creases in heart rate and blood pressure. Brain Res 1991;576: thyrotropin releasing hormone (TRH) and its antagonism by 101–110. Visual responses of the central nucleus of the amygdala during stress ulcer formation neurons in the dorsolateral amygdala of the alert monkey. Neuroanatomical cor- azepines mediated by a GABAergic mechanism in the amygdala. Psychol Bull cally conditioned response in hippocampectomized rabbits (Or- 1969;72:77–94. J Exp Psychol Anim Behav Process and basolateral amygdala encode expected outcomes during 1975;1:88–96. Neural encoding in text and space within the hippocampus: effects of complete, orbitofrontal cortex and basolateral amygdala during olfactory dorsal, and ventral excitotixic hippocampal lesions on condi- discrimination learning. LTP is accompanied by commensurate and the dorsal motor nucleus. Fear conditioning induces explicit and contextual cues. Neurons in the cortex of the temporal lobe and in explicit and contextual cues. Somatosensory and the mediation of conflict behavior in rats. Brain Res 1986;372: auditory convergence in the lateral nucleus of the amygdala. Central amygdaloid in- dependent formation of long-term potentiation in the rat medial volvement in neuroendocrine correlates of conditioned stress amygdala neuron in an in vitro slice prepartation. NMDA receptor antagonism in the lat- neuroendocrine, and behavioral effects of central amygdaloid eral/basolateral but not central nucleus of the amygdala prevents Chapter 64: Neural Circuitry of Anxiety and Stress Disorders 951 the induction of facilitated learning in response to stress. Fear, vigilance, and ambiguity: initial neuroimaging Mem 1998;5:220–230. Role of hippocampus in blocking and conditioned 177–188. Masked presentations of Physiol Psychiatry 1977;91:407–417. Greater fMRI activa- sponse to activation of the amygdala. Behavioural activation and excitatory amino acids in the basolateral amygdala: role in produced by CRH but not -helical CRH (CRH-receptor an- cardiovascular regulation. Nucleus accumbens and amyg- amygdala under stress-free conditions. Psychoneuroendocrinology dala are possible substrates for the aversive stimulus effects of 1995;20:423–432. The GABA/benzodiaze- hormone microinfusion in the central amygdala diminishes a pine receptor complex in the central amygdalar nucleus and cardiac parasympathetic outflow under stress-free conditions. Corticotropin-releasing induced behavior by antagonism of corticotropin-releasing fac- hormone microinfusion in the central amygdala enhances active tor in the central amygdala of the rat. A comparison of the effects amygdala does not induce any changes in cardiovascular, neu- of clonidine and CNQX infusion into the locus coeruleus and roendocrine or behavioural output in a stress-free condition. Enhanced behavioral control by condi- motor effects: localization of a sensitive site in the amygdala. Unit activity in the medial septum during differential Physiol Behav 1988;44:405–412. Brain Res 1991; J Comp Physiol Psychol 1981;95:331–340. Correlation of [3H]dia- immobilization-induced stress ulcers. Physiol Behav 1996;59: zepam binding density with anxiolytic locus in the amygdaloid 883–886. Neuropsychological correlates of bilat- substrates regulating rat conflict behavior evidenced by brain eral amygdala damage. Van de Kar LD, Piechowski RA, Rittenhouse PA, et al. Effects of sys- loid lesions: differential effect on conditioned stress and immo- temic and intra-amygdaloid diazepam on long-term habituation bilization-induced increases in cortiocosterone and renin secre- of acoustic startle in rats. Cryogenic blockade of the central ment of the bed nucleus of the stria terminalis and the central nucleus of the amygdala attenuates aversively conditioned blood nucleus of the amygdala in light-enhanced versus fear-poten- pressure and respiratory responses. This section provides succinct yet compre- Raze out the written troubles of the brain, hensive reviews of the most critical areas in mood disorders And with some sweet oblivious antidote, research by some of the leading investigators in the field. Cleanse the stuffed bosom of that perilous Each contribution highlights one or more major advances Stuff which weights upon the heart? William Shakespeare, Macbeth Thus, there is an appropriate emphasis on the longitudi- The advances in neurobiology documented comprehen- nal course of affective illness and a corresponding criticism sively elsewhere in this volume have been applied to no area of cross-sectional studies. With the maturation of psychiat- of research more so than affective disorders. This is not ric epidemiology and the Human Genome Project comes surprising, considering the magnitude of the public health anticipation of elucidation of both risk factors, and suscepti- problem these disorders represent and the long way yet to bility and resistance genes, respectively. The pathophysiol- ogy of these disorders is being scrutinized by a myriad of travel before an understanding of their pathophysiology is techniques ranging from cellular and molecular approaches, realized and optimal treatments are developed. Although to structural and functional brain imaging, to light and elec- the task is daunting, recent progress is heartening and in- tron microscopic neuroanatomic investigations. Major depression and bipolar disorder, the most techniques are being utilized to elucidate the mechanism common and severe of the mood disorders, are responsible of action of antidepressants, mood stabilizers, and newer for much of the suicide in the United States—now the treatments including rapid transcranial magnetic stimula- eighth leading cause of death, surpassing HIV infection, in tion, as well as to identify novel treatments including hor- the last 2 years. The Global Burden of Disease report, a mones and hormone antagonists. The data reviewing the collaborative effort of the World Health Organization and efficacy of current and novel treatments are presented, with the Harvard University School of Public Health, indicated the realization that too many patients are improved by the that depression would be the leading cause of morbidity in current treatment regimens, but far too few achieve com- the developing world in this next century. Appropriately, there is also attention to the and a fifth of all women in the United States will experience pharmacoeconomics of mood disorder treatment. It is now well I am grateful to all of the authors for their painstaking established that depression is an independent risk factor for contributions and accept all responsibility for any shortcom- ings in this section.

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Use of local anesthesia allows the patient to cough and strain during the procedure generic 150mg oxcarbazepine otc, to identify additional hernias as well as test the competency of the repair at the end of the surgery discount 600mg oxcarbazepine otc. This technique and its variations seem to be the preferred one for all cases of reducible and even voluminous or bilateral inguinal hernias oxcarbazepine 150mg mastercard. The technique is recommended for its safety, intra- and postoperative effectiveness on pain, reduced or absent 7. Inguinal Hernia Repair | 67 complications, low analgesic request, rapid reappraisal of the ability to walk and void, ease of perioperative management, shorter hospital stay, rapid discharge and economical convenience (Kark 1996, Kark 1998, Song 2000, Andersen 2005, Aasbo 2002). During local infiltration anesthesia, there is generally a low sedation requirement and potentially no need for anesthesiologist or nurse presence. These benefits are useful especially in the elderly and in patients with cardiac or pulmonary disease. IFB/LIA has also been associated with better postoperative pulmonary function tests (Gonullu 2002). High patient satisfaction scores have been reported as well (Callesen 2001). Despite these advantages, local infiltration anesthesia is rarely performed outside dedicated hernia centers and its use may be as low as 2% (Kettle 2001). Only about 60% of patients undergo this procedure in the ambulatory setting (Callesen 2001, Bay-Nielsen 2001). Limited learning of the technique is one of the most important causes. Another explanation may be intraoperative patient discomfort and pain. The surgeon must handle the tissues more carefully while operating because surrounding tissues, peritoneum and testis are not blocked. Although intraoperative pain is a real problem with the IFB/LIA technique, skilled and experienced surgeons can perform the operation even without the attendance of an anesthesiologist or nurse (Andersen 2005, Callesen 2001, Callesen 2001 (2)). A study referred that the majority of patients who received IFB/LIA experienced mild pain during the operation, though this was not measured, and a minority recorded some anxiety (Teasdale 1982). The problem of intraoperative discomfort may be underestimated because studies refer only the need for intraoperative rescue analgo-sedation and not pain scores. The use of sedation may be associated with increased 68 | Ultrasound Blocks for the Anterior Abdominal Wall patient satisfaction compared with unmonitored anesthesia (Song 2000). Finally, the traditional use of monitored anesthesia care with propofol and opioids or spinal and general anesthesia may have negatively influenced its diffusion (Callesen 2001, Toivonen 2004). A documented problem of the IFB/LIA is that it may require supplementary local anesthetic and sedation with moderate to high doses of benzodiazepines, requiring the attendance of an anesthesiologist (Ding 1995). IFB/LIA and IIB have not been evaluated in overweight and obese patients, where larger local anesthetic volumes are needed, although they are reported to be safe especially if the mixture is diluted. Moreover, a higher intensity of intra- and postoperative pain and a higher incidence of complications have been reported in obese patients (Nielsen 2005, Reid 2009). Some authors state that IFB/LIA of triple block performed before surgery is more time consuming, requires larger volume of the local anesthetic solution, does not always result in satisfactory anesthesia because of the blind nature of the procedure, and accidental needle puncture of the inguinal nerves may result in prolonged postoperative pain or neuropathic pain within their innervation field (Amid 1994). However, actual anesthesia block techniques offer selective nerve block achievement with low volumes of local anesthetic, direct visualization if ultrasounds are used, optimal pain control, fast recovery and discharge of patients and low analgesic requirements. A randomized study in children undergoing groin surgery performed to compare postoperative analgesia with IIB performed either percutaneously by the anesthesiologist before surgery or by the surgeon under intraoperative direct vision, revealed no statistical difference in pain scores between the groups (Trotter 1995). Inguinal Hernia Repair | 69 Iliohypogastric and Ilioinguinal Nerve Block Inguinal hernia is the type of surgery in which the IIB has been mostly practiced and studied. The IIB has been associated to monitored anesthesia care, general anesthesia or spinal anesthesia to decrease the initial pain after inguinal herniorrhaphy (Song 2000, Ding 1995, Andersen 2002, Aasbo 2002, Toivonen 2004, Toivonen 2001). A combined IIB together with an infiltration procedure may provide improved intraoperative analgesia, decreased requirements for additional sedation and monitoring and increased patient acceptance (Andersen 2005, Kehlet 2005). Many results indicate that IIB should be always performed after a general or spinal anesthesia. Moreover, preemptive IIB may be effective in decreasing postoperative analgesic requirements and prolonging the time to first rescue analgesia (Ong 2005). Ropivacaine for IFB and IIB under propofol and opioid analgo-sedation compared to general anesthesia with wound infiltration, resulted in a significantly more rapid transfer to the recovery unit and discharge, less need of analgesics during the first postoperative week and significantly faster and less painful reappraisal of normal activities (Aasbo 2002). The adding of IIB improves pain relief for 4 to 24 hours and reduces analgesic consumption compared to spinal and general anesthesia alone (Tverskoy 1990). Patients require the first opioid or non-steroid analgesic rescue significantly later and start to eat and mobilize sooner (Nehra 1995, Abad-Torrent 1997, Bugedo 1990). These benefits occur in spite of pain score differences at rest or in movement (Harrison 1994). The beneficial effects of IFB/LIA on pain scores, analgesic consumption and return to normal activities may last for 6 hours to up to 10 days (Narchi 1998, Murloy 1999, Bugedo 1990, Toivonen 2001). The factors contributing to delays in the time-to-home readiness include nausea, vomiting, inability to void, drowsiness, 70 | Ultrasound Blocks for the Anterior Abdominal Wall postural hypotension, post spinal headache, prolonged motor blockage, and administrative and social delays. General anesthesia is associated with a significantly higher incidence of sore throat, drowsiness, postoperative nausea and vomiting. A higher incidence of postoperative pruritus, urinary retention, lumbar backache and the longest time to achieve home discharge criteria occurs after spinal anesthesia (Song 2000, Toivonen 2004). Patients who receive IIB and spinal anesthesia have faster awakening and orientation times than patients who receive general anesthesia. Compared with standardized general and spinal anesthesia, IIB has been associated with lower pain scores at discharge, less analgesic requirement, a decreased time-to-home readiness, a lower incidence of side effects and lower total perioperative costs (Song 2000). Block group patients consumed more propofol than general anesthesia patients, but less fentanyl. In a retrospective study the use of IIB for patients undergoing herniorrhaphy resulted in no need for recovery room care (Yilmazlar 2006). Time to recovery and discharge criteria achievement is significantly lower even when a selective spinal anesthesia technique is performed (that has shorter recovery times compared to non selective spinal anesthesia), or subarachnoid opioid is associated (Poli 2009, Gupta 2003). Inguinal Surgery in Children Giulio Napoletano Inguinal surgery comprises inguinal hernia repair, orch- idopexy, orchiectomy, removal of cyst of the spermatic cord, ligation of patent processus vaginalis and hydrocelectomy. The blocks of the nerves of the abdominal wall have been evaluated in combination to general and spinal anesthesia and in comparison to multimodal analgesia. The IIB is among the most common (70% of all peripheral nerve blocks) used mainly for children between 4 and 7 years of age (Ban 2010). Inguinal hernia repair is the most frequent operation in which iliohypogastric and ilioinguinal nerve block is administered together with general anesthesia. The block appears to be safe and effective in reducing pain scores and analgesic request (Dalens 2001). However, the success rate may be as low as 70-80% with blind techniques and complications may occur (Lim 2002, Fell 1987). Intraoperative IIB decreases postoperative pain, analgesic use, and promotes early ambulation, recovery and discharge in children undergoing hernia repair. Simple infiltration of the wound with local anesthetic solution should be encouraged in pediatric anesthesia as it may become as effective as IIB. IIB has been shown to be more effective than simple wound infiltration for postoperative pain and analgesic request in inguinal surgery (Caetano 2006). Also, IIB associated with LIA may improve analgesia after inguinal surgery.

However oxcarbazepine 150 mg for sale, in The motor predominance of their clinical signs is in keeping this model -synuclein is not expressed in apoptotic pro- with the pathologic findings order oxcarbazepine 300mg mastercard, which indicate neuronal loss files; it is exclusively upregulated in normal-appearing neu- restricted to neurons of the SNpc and the locus coeruleus rons buy oxcarbazepine 600 mg overnight delivery, suggesting that it plays a role either in maintaining (146). Vila and co-workers (155) reached a simi- region, and a marker for this region, D6S305, was found lar conclusion in a model of chronic MPTP toxicity. Screening support of the possibility that -synuclein may play a role of complementary DNA (cDNA) libraries with a probe for in a plasticity response in these injury models is the observa- a putative exon, which was also deleted in this patient, led tion that -synuclein mRNA in SN is up-regulated during to the identification of a sequence encoding an open reading the first 4 postnatal weeks, a period of maximal differentia- frame for a 465amino acid protein (89). The deduced tion and synaptogenesis among DA neurons (85). What amino acid sequence of this protein contains a ubiquitin precise role -synuclein plays in the development of DA homology domain at the N-terminal, and a ring-finger neurons remains to be established. The gene encoding the protein is gous -synuclein null mice have thus far shown no obvious large [ 500 kilobase (kb)], and contains 12 exons. Deletion abnormalities in numbers or morphology of DA neurons; mutations were identified in four other affected patients density of striatal dopaminergic terminals; the number, in three independent families, confirming the pathogenetic morphology, or patch/matrix distribution of striatal neu- significance. These animals, however, do exhibit an in- pressed in various regions, including the SN (89). In addition, they show diminished behavioral activa- dividuals from 18 unrelated Japanese families revealed four tion following administration of amphetamine (4). The deletions affected exon has been a tendency to assume that the mutations cause a 3, exon 4, and exons 3 to 4, and a 1–base pair (bp) deletion toxic gain of function related to aggregation. It is important in exon 5resulted in a frameshift and an early stop. Further to keep in mind, however, that its function is unknown, and molecular analysis of non-Japanese families in Europe, re- that a loss of function may relate to disease pathogenesis. In vealed that in addition to deletion mutations, a variety of that regard, we have found that -synuclein mRNA levels point mutations resulting in either truncation or missense are diminished in the SNpc of patients with sporadic PD could also cause the phenotype (3). Markopoulou and colleagues (103) have shown in a identified patients with a late age of onset, up to 58 years 1786 Neuropsychopharmacology: The Fifth Generation of Progress in one case, and indicated that in some instances the clinical auto-oxidation of DA. This auto-oxidation generates toxic phenotype was indistinguishable from idiopathic PD (3). In addition, the pres- There is now growing recognition that mutations in par- ence of neuromelanin in the cell may alter the ability of kin may cause what clinically resembles idiopathic PD. In metal ions to participate in the production of reactive oxy- an investigation of the scope of the molecular and clinical gen species (145). Among early-onset patients without affected selectively destroy DA neurons—6-hydroxydopamine (6- family members, 18% had mutations. Many of the duce superoxide anion radical, H2O2, and hydroxyl radical. In all, 19 different rearrangements of exons mutations tions can be directed toward catecholamine neurons. More- were identified, including multiplications as well as dele- over, it can be limited to acting on DA neurons by pre- tions, and there were 16 different point mutations (101). By immunohistochemistry, the protein has been lo- Interestingly, like 6-OHDA, DA itself is a selective neu- calized at the regional level to SN and locus coeruleus, and rotoxin for DA neurons (38,54,61,62,114,135). This seems at the cellular level to the cytoplasm (139). Nuclear staining to be in large part due to its ability to oxidize to form was not observed. Parkin has been shown to play a role in reactive oxygen species, including DA quinone, which has protein degradation as a ubiquitin-protein ligase (140). Thus, it seems possible that DA itself can be a source teins or abnormal regulation of the half-life of normal cellu- of oxidative stress, particularly under conditions of increased lar proteins may play a role in cell death. DA turnover and decreased antioxidant defenses (see below). MPTP acts via its active product MPP , which is selec- PATHOGENETIC MECHANISMS tively taken up into DA neurons via the DA transporter, and inhibits complex I activity in mitochondria. Inhibition Free Radicals and Deficits in Energy of complex I not only interferes with adenosine triphosphate Metabolism (ATP) synthesis, but also results in augmented production The concept that free radical–mediated injury may underlie of superoxide anion radical. The possible role of superoxide the neuronal degeneration that occurs in PD has been, and radical in MPTP toxicity has received direct support by the continues to be, the leading hypothesis for its pathogenesis. This theory is also referred to as the oxidant stress hypothesis The free radical hypothesis of PD has also received sup- or the endogenous toxin hypothesis. In their review, Fahn port from studies of human postmortem brain. Free radicals and Cohen (34) point out that the free radical hypothesis can cause injury to cells by damaging DNA, proteins, and is appealing because four aspects of the neurochemistry of lipids of the cell membrane. There is evidence from post- DA neurons and their local environment within the SN mortem studies for free radical–induced modification of make the concept plausible. First, a major degradative path- each of these classes of molecules. Dexter and co-workers way for DA is its oxidative deamination by monoamine (24) have shown that in PD brain there is a reduction in oxidases A and B. This process results in the enzymatic levels of polyunsaturated fatty acids, which provide an index production of H2O2, which, while itself not a free radical, of the amount of substrate available for lipid peroxidation, can nevertheless react nonenzymatically with ferrous or cu- and an increase in levels of malondialdehyde, an intermedi- pric ions via Fenton-type reactions to form highly reactive ate in the lipid peroxidation process. Second, DA can react nonenzymatically dialdehyde was regionally specific for the SN. These workers with oxygen to form quinones and semiquinones, with the subsequently confirmed evidence for abnormal lipid peroxi- production of superoxide, hydrogen peroxide, and hydroxyl dation in PD by identifying a tenfold increase in cholesterol radicals. Third, the SN, particularly the SN pars reticulata, lipid hydroperoxide, an early marker in the lipid peroxida- is rich in iron, which as mentioned above, may in its ferrous tion process (25). Free radicals are also capable of directly state catalyze the formation of hydroxyl radicals from H2O2. The possibility that such stated above, it remains the foremost and most widely tested protein changes may also occur in PD brain is supported hypothesis of neural degeneration in PD. Nevertheless, it by the demonstration that protein adducts of 4-hydroxy-2- remains only a hypothesis, and it has its shortcomings (17). In addition, it must be remembered that nonaminergic neu- Postmortem studies have also revealed neurochemical ronal groups, such as the nucleus basalis, which is choliner- features that may predispose the PD brain to oxidative dam- gic, also degenerate in PD, and aspects of the free radical age. Reduced glutathione is an important endogenous anti- hypothesis that are dependent on catecholamine metabo- oxidant, and it has been reported to be reduced in the SN lism are not relevant to the degeneration of these structures. Jenner and colleagues (80) have confirmed low levels of reduced glutathione in the SN of PD patients, Programmed Cell Death and have shown that the alteration is disease-specific. Inter- estingly, they have also shown that reductions are observed The concept that a genetically regulated cell death process in patients with incidental Lewy body disease, which may may underlie the neuron-specific degenerations of later life be a preclinical form of PD (49). This finding suggests that has gathered great attention in recent years.

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A further specialization that contributes to spatial buffering is a nonuniform distribution of K channels on a single cell cheap 600mg oxcarbazepine. Because the end-foot of the Muller¨ cell buy oxcarbazepine 600mg overnight delivery, which abuts the vitreous humor of the eye purchase oxcarbazepine 600 mg on-line, has the highest density of K channels, accumulated [K ] is pref- FIGURE 10. Scheme showing how astrocytes are involved in o erentially transported to the vitreous, which acts as a dis- glutamate metabolism and uptake. Only astrocytes contain the enzyme glutamine synthetase, which converts glutamate to glu- posal site. It is not known if nonuniform K channel distri- tamine in an ATP-requiring reaction. Glutamine is transported to bution is a general feature of astrocytes. Finally, the released glutamate is recaptured o by astrocytes via a high affinity glutamate uptake system. Al- gray matter (to 60 to 80 mM) and white matter (to 12 though glutamate transporters are present in neurons, astrocytes to 15 mM in vitro) of the brain (27,47). The increases in are the most active in removing glutamate (see text). In the ab- sence of the normal transmembrane Na gradient, maintained [K ]o result because energy-dependent ion gradients can by the ATP-dependent Na pump, the glutamate transporter no longer be maintained and K entering the ECS can no ceases to remove glutamate and can run in reverse so that it longer be taken up by glial cells, which also depend on ATP pumps glutamate into the extracellular space (ECS). Glutamine is released by the glial cells and taken up sulfoximine produces a significant decrease in GABA pro- by the neurons through specific uptake carriers. In the pre- duction both in vivo and in brain slices (65%); however, synaptic terminal, glutamine is converted to glutamate because a 90% decrease in glutamine did not fully suppress through glutaminase, a phosphate-dependent enzyme pref- GABA synthesis, an additional metabolic source is consid- erentially localized to synaptosomal mitochondria (58,59). The newly synthesized glutamate is then packed into vesicles Astrocytes, it would seem, are essential for normal gluta- and becomes available for release. The glutamate-glutamine mate- and GABA-mediated synaptic transmission. Indeed, cycle is a clear and important example of cooperativity be- selective inhibition of glial cells in the guinea pig hippocam- tween astrocytes and neurons (Fig. It mediates re- pus using the glial-specific metabolic blocker, fluoroacetate, moval of potentially toxic excess glutamate from the extra- decreases transmission at glutamate synapses (66). Intracel- cellular space and provides the neuron with a synaptically lular recordings verified the integrity of neurons in fluoroac- inert precursor for resynthesis of glutamate. After a 6-min incubation of astrocytes in excitatory synaptic transmission is supported of slices of rabbit hippocampus in [14C] glutamine, half of by this study. Removal of glutamine from the bathing solution of the hippocampal Transmitter Removal slices decreased glutamate efflux by 60% to 80% after only 6 min (52). In addition to being the most important excitatory neuro- Not all of the glutamate taken up by astrocytes is directly transmitter in the brain, glutamate is also a potent neuro- converted to glutamine. Glutamate can also enter the TCA toxin and has been implicated in stroke, amyotrophic lateral cycle through its conversion to -ketoglutarate (KG). Highly efficient glutamate transport- enzymatic reactions can yield KG: one catalyzed by aspartate ers remove synaptically released glutamate and also keep the amino transferase and another by alanine aminotransferase, extracellular concentration of this amino acid at about 2 both reactions involving the transfer of an -amino group. Glutamate transporters are expressed in oligoden- The third reaction is the direct conversion of glutamate to drocytes, neurons, microglia, and astrocytes, but transport- KG via the action of glutamate dehydrogenase (60) (Fig. Theoretically, therefore, neurons might not get back regulating glutamate at synapses and in the extracellular in the form of glutamine (from astrocytes) all of the gluta- space (Fig. Two possibilities can be considered for stabiliz- appear to be predominantly localized in cerebellum and ret- ing the pool of vesicular glutamate in neurons. All have been cloned, functionally charac- trary to the preceding premise, astrocytes might be able to terized, and their localization and distribution at the re- compensate neurons for their loss of glutamate by appropri- gional, cellular, and subcellular levels in the CNS is known ate adjustments in glutamine export. A detailed review of this fertile field of research is because the pool of cytosolic glutamate in astrocytes is in beyond the scope of this chapter. Thus, EAAC 1 transport- equilibrium with TCA cycle intermediates, which in turn ers are neuronal, mostly localized on the cell body and den- can be replenished by the carboxylation of pyruvate derived drites, whereas GLAST and GLT-1 are predominantly glial from glucose. There are regional differences in the expression of be extracellular (glutamine), which would fluctuate in re- GLAST and GLT-1; GLAST is more heavily expressed in sponse to the needs of glutamatergic neurons. Second, re- the cerebellum and GLT-1 is more prevalent in the fore- cent data have demonstrated that neurons can generate glu- brain. Indeed, lactate produced by astrocytes in chemical gradients of Na and K , with a stoichiometry response to synaptically released glutamate (see the follow- of3Na and 1 H in and 1 K out with the uptake ing) appears to be taken up by neurons and could be a of each glutamate anion (55,69). The resulting increase in substrate for glutamate formation. One advantage of a system where in the brain, is synthesized from glutamate. Consequently, astrocytes take up most of the glutamate is that the meta- glutamine and -ketoglutarate are used for GABA synthesis bolic burden of this work is offloaded from neurons (55). Depolarization-released GABA is preferentially Several lines of evidence support that astrocytes play an synthesized from glutamine supplied by astrocytes (64). In- essential role in glutamate uptake in the brain (55): (a) As- hibition of astrocyte glutamine synthetase with methionine trocytes preferentially accumulate glutamate transporter Chapter 10: Astrocytes 137 substrate (71). Glutamate stimulates astrocytic Na-K-ATPase (81) by increasing intracellular Na concentration ([Na ] ) via 100-fold more vulnerable to glutamate toxicity (72). The overall stoichiometry levels of glutamate and neurotoxicity (73). Astrocyte membrane facing a gluta- mate synapse expresses higher levels of GLAST than mem- consumed through glycolysis produces two ATPs. One ATP is used by the Na /K ATPase for the extrusion of 3 Na ; brane facing other structures such as pia mater or capillaries (74). Most of the glutamate released at synapses appears to the other ATP could be used for the synthesis of glutamine be taken up by the adjacent astrocytes (75), although there from glutamate by glutamine synthase (Fig. The may be some regions in the brain where up to 20% of glutamate-stimulated glycolytic processing of glucose results glutamate is transported into the postsynaptic neuron (55). This scheme is, of increases both the amplitude and the duration of the excita- course, primarily relevant for synaptic regions of the brain tory postsynaptic current (76). Because axonal activity produces proportional in- creases in [K ] (28) and increases in [K ] increase astro- Metabolic Coupling with Neurons o o cyte glucose utilization (35,83), it is tempting to speculate Coupling of Synaptic Activity to Glucose that activity-dependent changes in [K ] in white matter o Utilization play an analogous role to glutamate release in gray matter. Is the lactate released by astrocytes in this model used The cytoarchitecture of astrocytes is of particular relevance as fuel by neurons? A vast array of experimental data indicate in a discussion about the coupling of synaptic activity to that in vitro, lactate in the absence of glucose can adequately glucose utilization. As mentioned, astrocyte end-feet sur- maintain synaptic (84–86) or axonal activity (87,88). If round virtually all brain capillaries, whereas other astrocytic astrocytes transfer lactate to neurons as a fuel source (Fig. In addition, astrocytes possess receptors and reup- priate enzymes for the creation of lactate in astrocytes and take sites for a variety of neurotransmitters, including the its use in neurons, and appropriate transport mechanisms excitatory neurotransmitter glutamate (77), whereas astro- for the movement of lactate. Indeed one isoform of lactate cytic end-feet are enriched in the specific glucose transporter dehydrogenase (LDH5), which is enriched in lactate-pro- GLUT-1 (6). Thus, astrocytes possess the necessary features ducing glycolytic tissues such as skeletal muscle, is predomi- to sense synaptic activity, through receptors and reuptake nantly localized in astrocytes in the human brain, whereas sites for neurotransmitters, and to couple it with the entry the other isoform, LDH1, expressed in highly oxidative tis- of glucose into the brain parenchyma (78). Experimental sues such the heart, which utilize lactate, is mostly found evidence supporting this function is reviewed here.