Joseph T. Coyle

Lesion of striatal neurons with kainic acid provides a model for Huntington's chorea

THE symptoms of Huntingtons chorea, an hereditary movement disorder, result from degeneration of neurones primarily in the basal ganglia1. Several neurochemical abnormalities have been identified in the brains of patients dying with this disorder2–5, but no animal system with similar neuropathological changes has been described. We now report that the injection of kainic acid into the rat striatum causes neuronal degeneration, neurochemical alterations and behavioural responses resembling Huntingtons chorea. This procedure could provide an animal model for the study of the disease.

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

D-serine added to antipsychotics for the treatment of schizophrenia

BACKGROUND Hypofunction of the N-methyl-d-aspartate (NMDA) subtype glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine, glycine, endogenous full agonists of the glycine site of the NMDA receptor (NMDA-glycine site), D-cycloserine, a partial agonist, or sarcosine, a glycine transporter-1 inhibitor, improves the symptoms of schizophrenia. D-alanine is another endogenous agonist of the NMDA-glycine site that might have beneficial effects on schizophrenia. METHODS Thirty-two schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-alanine (100 mg/kg/day), which was added to their stable antipsychotic regimens. Measures of clinical efficacy and side effects were determined every other week. RESULTS Patint who received D-alanine treatment revealed significant reductions in their Clinical Global Impression Scale and Positive and Negative Syndrome Scale (PANSS) total scores. The Scale for the Assessment of Negative Symptoms and PANSS subscores of positive and cognitive symptoms were improved. D-alanine was well tolerated, and no significant side effect was noted. CONCLUSIONS The significant improvement with the D-alanine further supports the hypothesis of hypofunction of NMDA neurotransmission in schizophrenia and strengthens the proof of the principle that NMDA-enhancing treatment is a promising approach for the pharmacotherapy of schizophrenia.

Neurobiology of Schizophrenia

With its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatments.

The Glutamatergic Dysfunction Hypothesis for Schizophrenia

&NA; Schizophrenia is a syndrome, undoubtedly with multiple etiologies, that variably exhibits several features including positive and negative symptoms, cognitive deficits, onset in young adulthood, and deterioration from the previous level of function. This review will examine the growing evidence that dysfunction of corticolimbic glutamatergic neurotransmission may contribute to or account for the manifestations of schizophrenia. Glutamatergic neurons represent the primary excitatory afferent and efferent systems innervating the cortex, limbic regions, and striatum. The postsynaptic actions of glutamate are mediated by a family of glutamate‐gated ion channels that permit the influx of sodium and calcium, thereby depolarizing (exciting) neurons. One of these receptors, the W‐methyl‐D‐aspartate (NMDA) receptor, is the site of action of psychotomimetics such as phencyclidine and related anesthetics, which can reproduce in normal individuals most of the symptomatic features of schizophrenia. An endogenous antagonist at the NMDA receptor, W‐acetyl‐aspartyl glutamate, appears to have enhanced activity in the frontal cortex and hippo‐campal formation in persons with this disorder. Glutamatergic dysfunction may be particularly relevant to those forms of schizophrenia in which negative symptoms, cognitive deficits, and deterioration are prominent features. In support of this inference, clinical studies have shown that drugs that enhance NMDA‐receptor function reduce negative symptoms and cognitive deficits in persons with chronic schizophrenia who are receiving neuroleptics. Thus, dysfunction of glutamatergic neurotransmission represents an important organizational focus for research on the complex manifestations of schizophrenia.

N-Acetylaspartate in neuropsychiatric disorders

N-Acetyl aspartate (NAA) is the second most abundant amino acid in the human brain. NAA is synthesized by L-aspartate N-acetyl transferase or by cleavage from N-acetyl aspartyl glutamate by N-acylated alpha-linked L-amino dipeptidase (NAALADase); and it is catabolized to acetate and aspartate by N-acetyl aspartate amino hydrolase (amino acylase II). NAA is localized primarily to neurons, where it is concentrated in the cytosol. Although NAA is devoid of neurophysiological effects, it serves as an acetyl donor, an initiator of protein synthesis or a carbon transfer source across the mitochondrial membrane. The concentration of NAA in human brain increases 3-fold between midgestation and adulthood. In Canavans Disease, an autosomal recessive disorder due to a null mutation in amino acylase II, NAA levels in brain are markedly increased and disrupt myelination. NAA levels have been found to be reduced in neurodegenerative disorders, including Alzheimers Disease and Huntingtons Disease. Since endogenous NAA can be readily detected in human brain by magnetic resonance spectroscopy, it is increasingly being exploited as a marker for functional and structural integrity of neurons in an expanding number of disorders.

Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia

Abstract: Numerous clinical studies demonstrate that subanesthetic doses of dissociative anesthetics, which are noncompetitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms, and brain functional abnormalities of schizophrenia. Postmortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo‐controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that hypofunction of a subset of NMDA receptors may contribute to the symptomatic features of schizophrenia.

Finding the intracellular signaling pathways affected by mood disorder treatments.

Postmortem and brain imaging studies have revealed structural changes and cell loss in cortico-limbic regions of the brain in bipolar disorder and major depression. Consistent with these findings, mood stabilizers such as lithium ion and valproic acid, which are used to treat bipolar disorder, as well as antidepressants and electroconvulsive therapy have recently been shown to activate interconnected intracellular signaling pathways that promote neurogenesis and synaptic plasticity. These insights should assist in understanding the pathophysiology of severe mood disorders as well as aid in the development of more effective treatments.

Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment

This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce neurodevelopmental effects at low doses. The results of this review demonstrate that the use of urinary 3,5,6-trichlorpyridinol (TCPy), a metabolite of chlorpyrifos as a biomarker of nonoccupational exposure is problematic and may overestimate nonoccupational exposures to chlorpyrifos by 10-to 20-fold because of the widespread presence of both TCPy and chlorpyrifos-methyl in the food supply. Current “background” (nonoccupational) levels of exposure to chlorpyrifos are several orders of magnitude lower than those required to inhibit plasma cholinesterase activity, which is a more sensitive target than nervous system cholinesterase. However, several in vitro studies have identified putative neurodevelopmental mechanisms that are altered at concentrations of chlorpyrifos below those that inhibit cholinesterases. Although one human cohort study reported an association between maternal and cord blood chlorpyrifos levels and several measures of neurodevelopment, two other cohort studies that utilized urinary TCPy as a surrogate for chlorpyrifos exposure did not demonstrate an association. Although the weight of the scientific evidence demonstrates that current levels of chlorpyrifos exposure will not have any adverse effects on neurodevelopment that might result from inhibition of nervous system cholinesterases, several recent studies propose alternative mechanisms. Thus, further in vivo investigation on neurodevelopment in an appropriate animal model is needed; additional epidemiological studies may be warranted if a suitable, chlorpyrifos-exposed cohort can be identified and more rigorous measures of exposure are utilized.

Tyrosine hydroxylase in rat brain—cofactor requirements, regional and subcellular distribution

Abstract A sensitive, radiochemical assay for tyrosine hydroxylase in rat brain is described. The enzyme is stimulated by catalase, dihydropteridine reductase and ferrous ion; maximal activity was found by homogenization in hypotonie buffer containing Triton X-100. Milligram quantities of rat brain tissue could be assayed at saturating concentrations of l -tyrosine. The enzyme is concentrated in the nerve terminal fractions as demonstrated by subcellular distribution studies. Seventy per cent of the activity can be released into the soluble fractions by hypotonie shock.