Tuning the engine of cognition: A focus on NMDA/D1 receptor interactions in prefrontal cortex

Castner, Stacy A.; Williams, Graham V.

doi:10.1016/j.bandc.2006.11.002

Cited by 115 publications

(95 citation statements)

References 279 publications

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“…gions that influences working memory performance (Castner and Williams, 2007) and attention (Granon et al, 2000). The hippocampus plays a crucial role in the formation of spatial reference memory (Morris et al, 1982;Poucet et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Disruption of the Ether-à-go-go K⁺Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Miyake¹,

Takahashi²,

Nakamura³

et al. 2009

J. Neurosci.

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The K ϩ channel, one of the determinants for neuronal excitability, is genetically heterogeneous, and various K ϩ channel genes are expressed in the CNS. The therapeutic potential of K ϩ channel blockers for cognitive enhancement has been discussed, but the contribution each K ϩ channel gene makes to cognitive function remains obscure. BEC1 (KCNH3) is a member of the K ϩ channel superfamily that shows forebrain-preferential distribution. Here, we show the critical involvement of BEC1 in cognitive function. BEC1 knock-out mice performed behavioral tasks related to working memory, reference memory, and attention better than their wild-type littermates. Enhanced performance was also observed in heterozygous mutants. The knock-out mice had neither the seizures nor the motor dysfunction that are often observed in K ϩ channel-deficient mice. In contrast to when it is disrupted, overexpression of BEC1 in the forebrain caused the impaired performance of those tasks. It was also found that altering BEC1 expression could change hippocampal neuronal excitability and synaptic plasticity. The results indicate that BEC1 may represent the first K ϩ channel that contributes preferentially and bidirectionally to cognitive function.

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Section: Discussionmentioning

confidence: 99%

Disruption of the Ether-à-go-go K⁺Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Miyake¹,

Takahashi²,

Nakamura³

et al. 2009

J. Neurosci.

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“…Although we are aware that the prefrontal cortex is only one part of a much larger and complicated circuit that governs cognitive functions, given the prominent role of glutamate in cognition, it is conceivable to hypothesize that such changes may contribute to learning and memory deterioration observed in humans after exposure to the drug (Zirnheld et al, 2004;Castner and Williams, 2007;Mouri et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Dynamic Regulation of Glutamatergic Postsynaptic Activity in Rat Prefrontal Cortex by Repeated Administration of Antipsychotic Drugs

et al. 2008

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Antipsychotics are the mainstay for the treatment of schizophrenia. Although these drugs act at several neurotransmitter receptors, they are expected to elicit different neuroadaptive changes at structures relevant for schizophrenia. Because glutamatergic dysfunction plays a role in the pathophysiology of schizophrenia, we focused our analysis on glutamatergic neurotransmission after repeated treatment with antipsychotic drugs. Rats were exposed to a 2-week pharmacological treatment with the first generation antipsychotic haloperidol and the second generation antipsychotic olanzapine. By using Western blot and immunoprecipitation techniques, we investigated the expression, trafficking, and interaction of essential components of glutamatergic synapse in rat prefrontal cortex. Prolonged treatment with haloperidol, but not olanzapine, dynamically affects glutamatergic synapse by selectively reducing the synaptic level of the obligatory N-methyl-D-aspartate (NMDA) subunit NR1, the regulatory NMDA subunit NR2A, and its scaffolding protein postsynaptic density 95 as well as the trafficking of subunit 1 of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor to the membrane. In addition, haloperidol alters total as well as phosphorylated levels of calcium calmodulin kinase type II at synaptic sites and its interaction with the regulatory NMDA subunit NR2B. Our data suggest that the glutamatergic synapse is a vulnerable target for prolonged haloperidol treatment. The global attenuation of glutamatergic function in prefrontal cortex might explain, at least in part, the cognitive deterioration observed in patients treated with haloperidol.

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“…As mentioned under Introduction, diminished dopaminergic and noradrenergic function in the cortex and HIP have been implicated in the pathophysiology of cognitive impairment, negative symptoms, and perhaps depression in patients with schizophrenia (Meltzer and McGurk, 1999;Millan, 2006;Juckel et al, 2006). Recent studies have clearly demonstrated the importance of increased cortical D 1 receptor stimulation for specific types of memory, including working memory and social memory (Castner and Williams, 2007;Nagai et al, 2007), possibly by increasing the activity of pyramidal neurons, modulation of glutamate NMDA receptor signaling at critical nodes within local circuits and distributed networks (Castner and Williams, 2007), fine tuning GABAergic interneurons (Kroner et al, 2007), and enhancing the release of cortical ACh (Di Cara et al, 2007). Thus, these effects on the efflux of cortical DA and NE may be clinically relevant to the treatment of schizophrenia (Ichikawa et al, 2001;Meltzer et al, 2003;Arnsten and Li, 2005), as well as to the ability of these same agents, in combination with at least some antidepressant drugs, to be effective in patients with major depression who fail to respond to antidepressant drug treatment alone (Shelton et al, 2001).…”

Section: Da Effluxmentioning

confidence: 99%

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

Huang

Dai

et al. 2008

Neuropsychopharmacol

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Atypical antipsychotic drugs, which are more potent direct acting antagonists of brain serotonin (5-HT) 2A than dopamine (DA) D 2 receptors, preferentially enhance DA and acetylcholine (ACh) efflux in the rat medial prefrontal cortex (mPFC) and hippocampus (HIP), compared with the nucleus accumbens (NAc). These effects may contribute to their ability, albeit limited, to improve cognitive function and negative symptoms in patients with schizophrenia. Asenapine (ASE), a new multireceptor antagonist currently in development for the treatment of schizophrenia and bipolar disorder, has complex serotonergic properties based upon relatively high affinity for multiple serotonin (5-HT) receptors, particularly 5-HT 2A and 5-HT 2C receptors. In the current study, the effects of ASE on DA, norepinephrine (NE), 5-HT, ACh, glutamate, and g-aminobutyric acid (GABA) efflux in rat mPFC, HIP, and NAc were investigated with microdialysis in awake, freely moving rats. ASE at 0.05, 0.1, and 0.5 mg/kg (s.c.), but not 0.01 mg/kg, significantly increased DA efflux in the mPFC and HIP. Only the 0.5 mg/kg dose enhanced DA efflux in the NAc. ASE, at 0.1 and 0.5 mg/kg, significantly increased ACh efflux in the mPFC, but only the 0.5 mg/kg dose of ASE increased HIP ACh efflux. ASE did not increase ACh efflux in the NAc at any of the doses tested. The effect of ASE (0.1 mg/kg) on DA and ACh efflux was blocked by pretreatment with WAY100635, a 5-HT 1A antagonist/D 4 agonist, suggesting involvement of indirect 5-HT 1A agonism in both the actions. ASE, at 0.1 mg/kg, increased NE, but not 5-HT, efflux in the mPFC and HIP. ASE, at 0.1 mg/kg (s.c.), had no effect on glutamate and GABA efflux in either the mPFC or NAc. These findings indicate that ASE is similar to clozapine and other atypical antipsychotic drugs in preferentially increasing the efflux of DA, NE, and ACh in the mPFC and HIP compared with the NAC, and suggests that, like these agents, it may also improve cognitive function and negative symptoms in patients with schizophrenia.

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Tuning the engine of cognition: A focus on NMDA/D1 receptor interactions in prefrontal cortex

Cited by 115 publications

References 279 publications

Disruption of the Ether-à-go-go K⁺Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Disruption of the Ether-à-go-go K⁺Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Dynamic Regulation of Glutamatergic Postsynaptic Activity in Rat Prefrontal Cortex by Repeated Administration of Antipsychotic Drugs

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

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Tuning the engine of cognition: A focus on NMDA/D1 receptor interactions in prefrontal cortex

Cited by 115 publications

References 279 publications

Disruption of the Ether-à-go-go K+Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Disruption of the Ether-à-go-go K+Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Dynamic Regulation of Glutamatergic Postsynaptic Activity in Rat Prefrontal Cortex by Repeated Administration of Antipsychotic Drugs

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

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Disruption of the Ether-à-go-go K⁺Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Disruption of the Ether-à-go-go K⁺Channel Gene BEC1/KCNH3 Enhances Cognitive Function