Bita Moghaddam

NMDA Receptor Hypofunction Produces Opposite Effects on Prefrontal Cortex Interneurons and Pyramidal Neurons

NMDA receptors mediate excitatory postsynaptic potentials throughout the brain but, paradoxically, NMDA receptor antagonists produce cortical excitation in humans and behaving rodents. To elucidate a mechanism for these diverging effects, we examined the effect of use-dependent inhibition of NMDA receptors on the spontaneous activity of putative GABA interneurons and pyramidal neurons in the prefrontal cortex of awake rats. We find that inhibition of NMDA receptors predominately decreases the activity of putative GABA interneurons but, at a delayed rate, increases the firing rate of the majority of pyramidal neurons. Thus, NMDA receptors preferentially drive the activity of cortical inhibitory interneurons suggesting that NMDA receptor inhibition causes cortical excitation by disinhibition of pyramidal neurons. These findings support the hypothesis that NMDA receptor hypofunction, which has been implicated in the pathophysiology of schizophrenia, diminishes the inhibitory control of PFC output neurons. Reducing this effect may be critical for treatment of schizophrenia.

From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment

Glutamate is the primary excitatory neurotransmitter in mammalian brain. Disturbances in glutamate-mediated neurotransmission have been increasingly documented in a range of neuropsychiatric disorders including schizophrenia, substance abuse, mood disorders, Alzheimers disease, and autism-spectrum disorders. Glutamatergic theories of schizophrenia are based on the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists to induce schizophrenia-like symptoms, as well as emergent literature documenting disturbances of NMDAR-related gene expression and metabolic pathways in schizophrenia. Research over the past two decades has highlighted promising new targets for drug development based on potential pre- and postsynaptic, and glial mechanisms leading to NMDAR dysfunction. Reduced NMDAR activity on inhibitory neurons leads to disinhibition of glutamate neurons increasing synaptic activity of glutamate, especially in the prefrontal cortex. Based on this mechanism, normalizing excess glutamate levels by metabotropic glutamate group 2/3 receptor agonists has led to potential identification of the first non-monoaminergic target with comparable efficacy as conventional antipsychotic drugs for treating positive and negative symptoms of schizophrenia. In addition, NMDAR has intrinsic modulatory sites that are active targets for drug development, several of which show promise in preclinical/early clinical trials targeting both symptoms and cognition. To date, most studies have been done with orthosteric agonists and/or antagonists at specific sites. However, allosteric modulators, both positive and negative, may offer superior efficacy with less danger of downregulation.

Bringing Order to the Glutamate Chaos in Schizophrenia

Recent genetic linkage studies complement the existing evidence that implicates abnormalities in NMDA receptor-mediated neurotransmission in the pathophysiology of schizophrenia. At the same time, advances in our understanding of the complex mechanisms that modulate the function of NMDA receptors suggest several novel sites for pharmacological manipulation of these receptors. This presents exciting opportunities for rational rather than serendipitous discovery of therapeutics for schizophrenia.

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.

Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.

Capturing the Angel in “Angel Dust”: Twenty Years of Translational Neuroscience Studies of NMDA Receptor Antagonists in Animals and Humans

Here, we describe our collaborative efforts to use N-methyl-d-aspartate (NMDA) receptor antagonists as a translational tool to advance our understanding of the pathophysiology of schizophrenia and identify potential new targets for treatment of schizophrenia. We began these efforts in the late 1980s with a keen sense that, in both human and animal studies, we needed to move beyond the dopamine hypothesis of schizophrenia; if the dopamine hypothesis were correct, the existing dopamine antagonists should have cured the disease but they have not. We used NMDA receptor antagonists, not to produce schizophrenia, but as a tool to provide insights into effects of disturbances in glutamate synaptic function in schizophrenia. Our work has provided insights into potential mechanisms that may contribute to disrupted cortical function in schizophrenia and has helped identify potential treatment targets for the disorder. The translational nature of this study made the clinical testing of the first of these targets feasible. Advances in systems neuroscience approaches in animals and humans make new types of translational research possible; however, our concern is that the current obstacles facing translational research funding and academia-industry collaborations threaten the future progress in this field.

The Neurobiology of Adolescence: Changes in brain architecture, functional dynamics, and behavioral tendencies

Adolescence is a period of increased behavioral and psychiatric vulnerabilities. It is also a time of dramatic structural and functional neurodevelopment. In recent years studies have examined the precise nature of these brain and behavioral changes, and several hypotheses link them together. In this review we discuss this research and recent electrophysiological data from behaving rats that demonstrate reduced neuronal coordination and processing efficiency in adolescents. A more comprehensive understanding of these processes will further our knowledge of adolescent behavioral vulnerabilities and the pathophysiology of mental illnesses that manifest during this period.

Transient N-Methyl-D-Aspartate Receptor Blockade in Early Development Causes Lasting Cognitive Deficits Relevant to Schizophrenia

BACKGROUND Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission has been implicated in schizophrenia. We studied whether transient inhibition of NMDA receptor activity during early postnatal development would produce a behavioral phenotype resembling that of individuals who are susceptible to develop schizophrenia. METHODS Rat pups were given injections of the NMDA channel blocker MK801 on postnatal days 7 through 10. This period is akin to the prenatal second trimester of primate development. Cognitive function was tested in adulthood. RESULTS Treatment with MK801 impaired cognitive flexibility and working memory. The impairment in cognitive flexibility was due to increased perseverative behavior. Treatment did not affect locomotor activity or recognition memory. CONCLUSIONS These results suggest that a brief disruption of NMDA receptors during a sensitive period of cortical development is sufficient to produce selective cognitive deficits that are relevant to schizophrenia.

Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm.

Our earlier study demonstrated that Coeloglossum viride (L.) Hartm. var. bracteatum (Willd.) extract (CE) significantly improved the impaired memory in mice caused by permanent two-vessel occlusion. To investigate whether chronic treatment with CE could influence cerebral ischemia-induced neuronal and cognitive impairments, we examined the effects of CE on two different kinds of cerebral injury: transient middle cerebral artery occlusion model of focal cerebral ischemia; four-vessel occlusion model of transient global forebrain ischemia. CE treatment (5 mg/kg, orally) significantly reduced lesion volume, and improved the performance of passive avoidance and rotarod motor tasks in transient middle cerebral artery occlusion rats. In the four-vessel occlusion model, neuronal cell loss in CA1 of hippocampus was significantly decreased and the performance in the Morris water maze was significantly improved in rats administered CE. We conclude that treatment with CE attenuated learning and memory deficits, motor functional disability, and neuronal cell loss induced by global or focal cerebral ischemia. These results suggest that CE may be a potential candidate for the treatment of vascular dementia.

Rule Learning and Reward Contingency Are Associated with Dissociable Patterns of Dopamine Activation in the Rat Prefrontal Cortex, Nucleus Accumbens, and Dorsal Striatum

The midbrain dopamine system has been ascribed roles in reward expectancy, error detection, prediction, and memory. However, these theories typically do not differentiate between dopamine response and action in different forebrain terminal fields. We measured dopamine release in the prefrontal cortex (PFC), nucleus accumbens (NAc), and dorsal striatum (DS) of rats exposed to the same maze apparatus under three behavioral conditions: a set-shift task in which reward depended on discrimination learning and extradimensional set-shifting, a yoked condition in which reward was intermittent and not under the control of the subject, and a “reward-retrieval” variant in which reward was certain on every trial. We found dissociable patterns of dopamine release associated with learning, uncertainty, and reward. Dopamine increased in all three regions when reward was contingent on rule learning and shifting or was uncertain. These increases were sustained after behavior. There was a significant correlation between the magnitude of increase in PFC dopamine and the rapidity with which rats shifted between discrimination rules. In the yoke condition, in which the receipt of reward was always uncertain, the opposite relationship between dopamine levels and likelihood of reward was observed. Predictable, noncontingent reward was associated with increased dopamine levels in the NAc and DS. In contrast, PFC dopamine did not increase significantly above baseline levels. Thus, the dopaminergic projections to the PFC and nucleus accumbens were selectively, yet differentially, activated in situations of uncertainty and cognitive demand, whereas the dopaminergic projection to the DS responded independently of task differences in learning and reward.