Neurochemical Mechanisms in Disease P23 ppt

Glutamate and Glutamine in Brain Disorders 205 of dopaminergic pathways and cause Parkinsonism) treatment of cats and NMRS analysis found lower [glutamate+glutamine]/[creatine] ratio than in control animals (Podell et al., 2003). Chronic treatment with the mitochondrial toxin 3-nitropropionic acid (3-NPA; inhibits succinate dehydrogenase, a TCA cycle enzyme) induces lesions in the stria- tum of animals leading to symptoms similar to Huntington’s disease in humans (Brouillet et al., 1998). Initial, acute intoxication with 3-NPA in mice selectively targeted GABAergic neurons inhibiting their TCA cycle, whereas glutamatergic pathways, glial cells, and glutamate–glutamine cycle function were unaffected (Hassel and Sonnewald, 1995). However, this selective inhibition of (GABAergic) neuronal function in the striatum is still somewhat of a mystery, as 3-NPA affects other brain regions as well (Brouillet et al., 1998) showing a general 18% decrease in TCA cycle flux in one in vivo NMRS study of rat brain (Henry et al., 2002). In conclusion, glutamate and glutamine homeostasis seem to play a role in neurodegenerative pathologies, although the picture is not consistent. Much more research is needed to elucidate the potential role of malfunction of glutamate and glutamine homeostasis in neurodegenerative disorders. Especially, ex and in vivo NMRS employing animal models as well as patients should be employed to this end, as such approaches provide the most precise information. 3.4 Psychiatric Disorders The psychiatric disorders represent a duality of suffering for the patients, as they not only have to combat the disease but also have to endure the stigmatization of being mentally ill. Thus, not only is there a need for effective pharmacotherapy and research into the pathogenesis, there is also a need for changing the public view on these disorders. There is increasing evidence that glutamate/glutamine homeostasis is disturbed in a number of psychiatric disorders. Thus, in the anterior cingulate cortex, GDH and GS were found to be expressed to a lower extent in patients suffering from bipolar disorder and major depressive disorder, respectively (Beasley et al., 2006). Conversely, it was found that transcripts (i.e., mRNA) for PAG and GS are present to a higher extent in the thalamus of patients suffering from schizophrenia and, in addition, increased transcripts for the glial glutamate transporters (EAAT1, EAAT2) as well as a vesicular glutamate transporter (VGLUT2) have been reported (Smith et al., 2001a, b). Furthermore, one study suggests that EAAT2 protein may actu- ally be increased in prefrontal cortex of schizophrenic patients and that atypical antipsychotic pharmacotherapy (e.g., clozapine) may normalize the expression of EAAT2 protein (Matute et al., 2005). In this respect, it should be noted that such “hyperactive” astrocytic glutamate transport may constitute a target for novel phar- macotherapeutic approaches, as discussed by Nanitsos et al. (2005). As always, mRNA levels may not reflect actual formation of functional protein and, moreover, when using patients there is always the risk that treated and nontreated patients as well as the stage of the disease may affect the results. The last point is illustrated 206 L.K. Bak et al. by the study of Ohrmann et al. (2005) in which only chronic but not first-episode patients showed significantly lower glutamate/glutamine levels in the prefrontal cor- tex. Interestingly, another study published the same year by another group did not find such differences and, quite disturbingly, they found the opposite effect on the glutamate and glutamine levels, that is, increased concentrations in both prefrontal cortex and hippocampus (van Elst et al., 2005). This may illustrate the complexity of such diseases, and one way to investigate this under more controlled conditions is to turn to animal models. In general, animal models of psychiatric disease are somewhat of a conun- drum, as symptoms are usually subjective; for example, in schizophrenia, symptoms consist of so-called positive (thought disorder; delusions) and negative symptoms (emotional disorder). One potential high-quality animal model of schizophrenia producing both negative and positive symptoms is based on the glutamate hypo- function hypothesis and may be induced by treating rats with the noncompetitive, activity-dependent N-methyl-D-aspartate (NMDA) receptor blocker MK-801 (or dizocilpine; the systematic IUPAC name is [5R,10S]-[+]-5-methyl-10,11-dihydro- 5H-dibenzo[a,d]cyclohepten-5,10-imine; Carlsson et al., 2001). MK-801 was orig- inally being developed by the drug company Merck & Co. as a neuroprotective agent but was discontinued because of the above ability to induce cellular lesions, eventually leading to schizophrenic symptoms (Olney et al., 1989). Eyjolfsson et al. (2006) argues, that repeated “low” doses (0.1 mg/kg) of MK-801 mimics some of the typical behavioral changes observed in schizophrenic patients (e.g., hyperloco- motion) whereas neurochemical changes consistent with observations in so-called first-episode patients (Kondziella et al., 2006) were only present after repeated “high” doses (0.5 mg/kg). A single dose (0.5 mg/kg) of MK-801 given to rats that were subsequently injected with [1-13C]glucose and [1,2-13C]acetate in combination, caused an increase in total glutamine content as well as in [4-13C]glutamine synthesized from [1-13C]glucose (Brenner et al., 2005); the mechanism may involve decreased NO- mediated inhibition of GS (Kosenko et al., 1995, 2003). In the study by Brenner et al. (2005), no concomitant increase in [4-13C]glutamate was observed which indi- cates that the glutamate–glutamine cycle may be affected in the neuron-to-astrocyte direction; however, labeling from [1,2-13C]acetate in glutamate, glutamine, and GABA were not altered, suggesting that the flow of glutamine from astrocytes to neurons was not influenced by a single injection of MK-801. In contrast, another study by the same group employing repetitive injections of MK-801 (0.5 mg/kg; rats; every day for 6 days) showed decreased synthesis of [4,5-13C]glutamate and [4,5-13C]glutamine from [1,2-13C]acetate in the prefrontal cortex (Kondziella et al., 2006) implying that the glutamate–glutamine cycle is impaired in the astrocyte-to-neuron direction in this model. As suggested by Kondziella et al. (2006) as well as Eyjolfsson et al. (2006), repeated injections rather than a single injection of MK-801 may be a better animal model, as the neurochemical and behavioral changes are more in keeping with the changes observed in patients. In conclusion, psychiatric disorders seem to involve a significant component of disruption of glutamate/glutamine homeostasis. In addition, a high-quality Glutamate and Glutamine in Brain Disorders 207 animal model of schizophrenia based on repetitive injections of MK-801 has been established and might prove to be of significant value in future research. 4 Potential Drug Targets Related to Glutamate and Glutamine Homeostasis Clearly, interfering with glutamate/glutamine homeostasis s eems an attractive goal to pursue for symptomatic treatment of a number of brain disorders. In the treatment of epilepsy, drugs targeting GABA transporters (tiagabin) and GABA-transaminase (vigabatrin) have been on the market for a number of years, providing proof of principle for the neurotransmitter cycling systems as pharmacological targets (Sarup et al., 2003). However, with regard to glutamate homeostasis no such drugs have been marketed, although one effect of atypical antipsychotic pharmacotherapy may be a reduction in astrocytic EAAT2 protein (Matute et al., 2005) and it has been suggested that a novel approach in treating psychotic disease should be directed specifically at regulating astrocytic glutamate transport “hyperfunction” (Nanitsos et al., 2005). One concern with targeting the glutamatergic neurotransmitter system might be that glutamatergic synapses are so abundant and that glutamate is an impor- tant metabolite in intermediary metabolism, making interference with glutamate homeostasis a potential nightmare with regard to adverse effects. Thus, most drug development directed at the glutamatergic system seems to have been focused on ionotropic glutamate receptors as pharmacological targets, although G-protein coupled receptors have been attracting increased attention. Recent work by Rae et al. (2005) shows that metabotropic glutamate receptors might constitute attractive drug targets for regulating the metabolism associated with the glutamate–glutamine cycle. Agonists and antagonists of metabotropic glutamate receptors of groups I and II (coupled to the phosphoinositide/Ca2+ and the cyclic AMP second messenger systems, respectively) affected TCA cycle activity as well as the glutamate– glutamine cycling rate in Guinea pig slices. It was observed that group I ago- nists/antagonists affected TCA cycle activity, whereas group II agonists/antagonists influenced the glutamate–glutamine cycling rate. Thus, metabolic homeostasis of the glutamate/glutamine system may be a fertile avenue to pursue in order to identify novel targets for pharmacotherapy directed at a number of diseases of the brain. 5 Concluding Remarks It seems clear from this discussion that metabolic changes related to glutamate and glutamine homeostasis are an integral part of many pathologies of the brain and that interfering with the glutamate/glutamine system may be an attractive tar- get for drug treatment. However, much work still needs to be performed in order to elucidate the many aspects of metabolic dysfunction in neurological and psy- chiatric diseases. Especially, increased use of in vivo MR spectroscopy will be 208 L.K. Bak et al. important in this respect to elucidate the complex metabolic changes in patients and animal models of brain disease. However, although employing 13C-labeling and spectroscopy techniques may aid in mapping metabolic dysfunctions, the exact mechanisms underlying these disturbances need to be addressed as well. The best way to bring this about is to employ a different set of techniques including pro- teomics methodology to determine changes in the related proteome. Furthermore, refinement of existing, and development of new, animal models of brain diseases are an important issue. This may become easier as knowledge of potential genetic and/or developmental causes of brain disease becomes available, making genetically modified animals the model of choice for these investigations. No doubt, the future will bring an increased appreciation of the metabolic disturbances involved leading to an improved understanding of the pathology of brain disorders. 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Biol Psychiatry 58:724–730 Rho-Linked Mental Retardation Genes Nael Nadif Kasri and Linda Van Aelst Abstract Mental retardation (MR) is generally defined as a global reduction in cognitive abilities, which manifests before the age of 18. The causes of MR are extremely heterogeneous, including environmental factors as well as genetic changes, such as chromosomal abnormalities and single-gene mutations. Great progress has been made in recent years towards the identification of MR genes, par- ticularly X-linked MR genes. A largely remaining challenge, however, is to connect the genetic causes of MR to processes that establish and/or modify neuronal cir- cuit function. Several of the currently identified genes are associated with MR code for regulators and effectors of the Rho subfamily of GTP-binding proteins, which are key regulators of the actin cytoskeleton. The identification and characterization of Rho-linked genes associated with different forms of MR have shed light on our current understanding as to how defective cellular signaling can result in abnor- mal neuronal connectivity, which can give rise to impaired information processing underlying cognitive function. Aberrations in defined Rho-mediated signaling path- ways have been linked to defects in the formation and remodeling of dendritic spines and/or the maturation and activity-dependent modification of the efficacy of synapses. In this review, we focus on the role of Rho GTPases and their asso- ciated signaling molecules in the control of spine structure and synaptic function, and highlight their involvement in MR resulting from a variety of genetic mutations within regulators and effectors of these molecules. Keywords Mental retardation (MR) · Dentritic spines · Synaptic structure and function · Actin cytoskeleton · Rho GTPases · Rho-linked MR genes · Nonsyndromic and syndromic X-linked MR · Autosomal syndromic MR Contents 1 Mental Retardation 214 1.1 Definition, Causes, and Classification 214 L. Van Aelst (B) Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA e-mail: vanaelst@cshl.edu 213 J.P. Blass (ed.), Neurochemical Mechanisms in Disease, Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_8, C  Springer Science+Business Media, LLC 2011 214 N.N. Kasri and L. Van Aelst 1.2 Mental Retardation Is Associated with Abberations in Spine Structure and Synaptic Function 215 2 Rho GTPases 217 2.1 Rho GTPases Control Synaptic Structure and Function 217 2.2 Mutations in Regulators and Effectors of Rho GTPases Underlie Various Forms of Mental Retardation 221 3 Conclusions 232 References 232 1 Mental Retardation 1.1 Definition, Causes, and Classification Mental retardation (MR) is generally defined as a global reduction in cognitive and intellectual abilities, which manifests before the age of 18, and is estimated to affect 1 to 3% of the population (Chelly et al., 2006). Intellectual functioning and its severity is commonly based on the evaluation of the Full Scale Intelligence Quotient (FSIQ), and MR is represented by an intelligence quotient (IQ) lower than 70. Based on the IQ, MR is commonly classified in two main groups: severe MR with an IQ below 50, and mild MR with an IQ between 50 and 70. The causes of MR are extremely heterogeneous and include nongenetic factors such as premature birth, infectious disease, and fetal alcohol syndrome, as well as genetic changes that include chromosomal abnormalities and single-gene mutations (Mandel and Chelly, 2004; Ropers and Hamel, 2005; Vaillend et al., 2008). Conventionally, genetic forms of MR have been subdivided into syndromic and nonsyndromic forms; with syndromic MR being characterized by associated clinical, radiological, metabolic, or biological features whereas in the case of nonsyndromic or nonspecific MR, cognitive impairment represents the only manifestation of the disease (Chelly and Mandel, 2001; Ropers and Hamel, 2005). It should be noted, however, that more recent genotype/phenotype studies and clinical re-evaluations of patients indi- cate that the boundaries between syndromic and nonsyndromic MR are vanishing. Moreover, several of the MR-related genes emerged as being involved in both forms of MR (Frints et al., 2002; Chelly et al., 2006). Great progress has been made in recent years towards the identification of MR- related genes, resulting in a list of approximately 300 genes. A complete list of MR- and associated syndromes-related genes has been rigorously reviewed by Inlow and Restifo (Inlow and Restifo, 2004). Among these genes, several are associated with severe brain abnormalities, such as neuronal heterotopia, lissencephaly, and micro- cephaly (Chelly et al., 2006). In these cases, MR is likely to be a secondary symptom inasmuch as the involved gene products are likely to play a role in proper develop- ment of the CNS. A vast number of other genes have been associated with MR dis- orders with no apparent/gross abnormalities in brain structure and architecture, and, as discussed below, current efforts are geared towards unraveling the cellular bases for these MR conditions. Whereas the initial excess in identifying genes mutated . toxin 3-nitropropionic acid (3-NPA; inhibits succinate dehydrogenase, a TCA cycle enzyme) induces lesions in the stria- tum of animals leading to symptoms similar to Huntington’s disease in humans (Brouillet. changes in patients and animal models of brain disease. However, although employing 13C-labeling and spectroscopy techniques may aid in mapping metabolic dysfunctions, the exact mechanisms underlying. pentylenetetrazole-kindling model of epilepsy in SAMP8 mice: glial-neuronal metabolic interactions. Neurochem Int 43:629–637 Kosenko E, Kaminsky Y, Grau E, Minana MD, Grisolia S, Felipo V (1995) Nitroarginine, an