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D1 receptors in prefrontal cells and circuits
Brain Research Reviews 31 Ž2000. 295–301 www.elsevier.comrlocaterbres
Interactive report
D 1 receptors in prefrontal cells and circuits
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P.S. Goldman-Rakic ) , E.C. Muly, III, G.V. Williams Yale UniÕersity School of Medicine, Neurology Section, P.O. Box 208001r SHM B404, 333 Cedar Street, New HaÕen, CT 06510-8001, USA Accepted 7 August 1999
Keywords: Primate; Non-human primate; Working memory; Conition; Delayed response; Inhibitory; Interneuron; Pyramidal neuron
Contents 1. Introduction .
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2. Dopamine and cognition
3. Dopamine modulation of mnemonic function in prefrontal neurons .
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4. The D1 receptor in pyramidal neurons 5. D1 mechanisms in interneurons
6. Feedforward inhibition model of dopamine action vis a vis cognitive circuitry . References
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1. Introduction A worthy goal of systems neuroscience is to dissect the cellular and circuit basis of behavior in order to extend the insights gained from the study of normal brain organization in animal models to an understanding of a clinical disorder. We have been employing this strategy to elucidate the organic basis of the cardinal symptoms of schizophrenia, including the thought process in this disorder. Our studies are based on the hypothesis that many features of schizophrenia represent a failure in the neural mechanisms by which prefrontal cortex stores and processes information in working memory w1,2x. From the broadest perspective, working memory is a system of operations for processing information in real time, i.e., on a moment to moment basis, and even subtle deficiencies in the machinery of working memory can mean substantial ) Corresponding author. Tel.: q1-203-785-4808; Fax: q1-203-7855263; E-mail: [email protected] 1 Published on the World Wide Web on 9 November 1999.
deficits in ideation, reasoning and planning such as are observed in psychosis w2x. Disturbances in the finely tuned mechanisms of temporal integration that are essential to working memory may also be at the core of impairments which are less obviously cognitive, such as smooth pursuit eye tracking and pre-pulse inhibition. In the past decade, major advances have been made in our capacity to decipher the elemental basis of working memory processes as they operate in the prefrontal cortex of macaque monkeys. We and others have been able to characterize the functional properties of prefrontal neurons as they are specialized for particular operations in working memory such as encoding a specific stimulus, maintaining it ‘on line’ and directing an appropriate memory-guided response. These studies have shown that prefrontal neurons are remarkably content specific, i.e., individual neurons encode and transiently store specific items of information, such as the location of an object w3,4x, the direction of a prior response w5x, the identity of objects or faces w6,7x and the identity of voices and sounds w58x. These prefrontal neurons and the mechanisms which endow them with the
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capacity to represent a stimulus in its absence, have become a major focus of our interest. In this chapter, we describe our efforts to understand the pyramidal and nonpyramidal cells of the prefrontal cortex, the area of the brain most associated with the working memory functions of the brain. We also address the circuit and receptor mechanisms which regulate pyramidal and nonpyramidal cell excitability in vivo. Specifically, we review our studies on the dopamine modulation of working memory circuits. This work may seem far afield from the clinical disorder of schizophrenia, but we hope to demonstrate that a connection may exist between the disposition of neurotransmitter receptors in individual neurons and behavioral symptoms, and that such a connection may illuminate the biological basis of this disease.
ies, the anatomical precision of immunohistochemistry and in situ hybridization and not least, the development of sophisticated behavioral paradigms, are among the major advances that have made understanding dopamine’s role in cognition a reasonable goal. All of these approaches have been applied to the analysis of the anatomical and functional architecture of the dopaminergic innervation of the prefrontal cortex in our laboratory. As the micro-columnar architecture of prefrontal cortex is repeated in most other regions of the cerebral cortex, the mechanisms elucidated in this area have a high likelihood of revealing general principles of dopamine modulation applicable to other cortical areas.
3. Dopamine modulation of mnemonic function in prefrontal neurons 2. Dopamine and cognition Cognitive symptoms have been associated with dopamine dysregulation in numerous diseases including Huntington’s disease w8x, schizophrenia w9x, depression w10x, drug addiction w11x, and Parkinson’s Disease w12x as well as in normal aging w13x. This neurotransmitter has been linked to a wide variety of functions including motivation, reward, affect and movement, all of which could affect performance on cognitive tasks without affecting the brain’s information processing systems per se. Nevertheless, a variety of studies in experimental animals along with a plethora of neuropsychological studies in clinical populations suggest a direct association between altered dopamine transmission in the prefrontal cortex and cognitive deficits w14,15x. The cloning of five distinct dopamine receptors, the development of receptor-specific ligands and antibod-
The cellular basis of receptive field properties is among the most challenging issues in the study of higher cortical function. To date, neurotransmitter-specific actions on cortical neurons have been confined largely to examination of in vitro systems. Now, very recently, we have developed the methods to analyze the pharmacological actions of drugs on neurons as they are engaged in cognitive processes in awake behaving animals. With this method we have shown that the ‘memory fields’ of prefrontal cortex are modulated by neurotransmitters such as dopamine w16x, serotonin w59x, and the inhibitory neurotransmitter, gamma-amino-butyric acid ŽGABA. in distinctively different ways w17x. This is significant not only because they reveal the endogenous modulators of cognition on normal processes but also because dysfunction in dopamine, serotonergic, andror GABAergic neurotransmission has been
Fig. 1. Dose-dependent effects of the selective D1 antagonist SCH 39166 on activity of a prefrontal neuron. Top: Control recording showing significant delay period activity Žfor the preferred target direction of 08.. Middle: SCH 39166 Ž25 nA. induces dramatic enhancement of delay activity selectively, without any increase in the background activity of the cell. Bottom: At a high dose Ž75 nA., SCH 39166 abolishes activity during the delay period as well as other periods of the task. Note: C s cue period Ž0.5s., D s delay period Ž3.0s., R s response period Žbin s 50 ms.. Drug used at 10 mM, pH 3.5–4.0. wFrom 16x.
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implicated in many disorders of cognition. We have begun to study the actions of these neurotransmitters with respect to the localization of the relevant receptors within the cortical micro-architecture. In particular, we have shown that D 1 receptors can modulate excitatory transmission in neurons which are involved directly in the mnemonic component of the task ŽFig. 1. w59x. The spatial tuning of prefrontal neurons engaged in spatial working memory is enhanced at moderate levels of D 1 occupancy and reduced at both lower and higher levels of occupancy. The specificity of drug action on single cell activity may be accounted for by the specific synaptic arrangement of D 1 receptors in spines that receive excitatory inputs, presumably from the visual pathways carrying highly processed visuospatial information w18,19x. These findings may be relevant to clinical conditions. It is of interest that a recent PET study has revealed that the D 1 receptor is decreased in the prefrontal cortex of both medicated and non-medicated schizophrenic patients. In addition, the density of D 1 receptors was positively correlated with performance of the patients on the Wisconsin Card Sort Task w20x. Normal aging also brings with it a decline in dopamine levels and D1 receptor function w21– 23x and in working memory w13,24x. Given the vulnerability of cognitive functions to dopamine dysfunction, it would not be surprising if a common pathophysiological process were responsible for the cognitive deficits in Parkinson’s disease, aged individuals and schizophrenic patients. In our model, as illustrated in Fig. 2, there is an optimal level of D 1 receptor occupancy for efficient physiological signaling and optimal performance. This raises the possibility that neuroleptic resistance of both negative symptoms and cognitive dysfunction in schizophrenic patients may be related to an abnormality of D 1 function. Support
Fig. 2. Diagram illustrating the biphasic modulation of working memory function by dopamine was revealed in 16x. At extremely low levels of dopamine and D1 receptor activation, as might occur in Parkinson’s disease, there would be no dopaminergic facilitation of functional glutamatergic inputs to prefrontal neurons. The consequent absence of memory fields, as indicated by the effects of high levels of D1 antagonists in iontophoretic studies, should result in loss of working memory. In this condition, D1 agonists should be capable of reinstating memory fields. As dopamine levels rise they enter a normal range in which there is an optimum level of D1 receptor activation for the generation of memory fields. A high level of motivation was required to perform the ODR task which would account for dopamine levels being near the high end of the range and for the improvement of memory fields by low levels of D1 antagonists. If dopamine levels rise further, beyond this range, due to severe stress or acute amphetamine administration, then D1 receptor activation produces an increasing level of inhibition of selective glutamatergic inputs to prefrontal cells. This should lead to dissipation of memory fields, as suggested by the effects of iontophoresis of D1 agonists in the present study, and a subsequent loss of working memory. In this opposite extreme the memory fields should be reinstated by D1 antagonists. wFrom 25x.
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for this possibility is provided by two recent findings from this laboratory: D 1 message and protein in the prefrontal cortex of rhesus monkeys is down-regulated by chronic neuroleptic treatment w25x; and the same treatment that lowers the level of D 1 receptors produces impairments in working memory performance w60x. We conclude from these and other observations that cortical dopamine regulates cognitive processing via its action at D 1 receptors. This may translate to a dampening and disruption of information flow in the cortico-striato-tectal and corticostriato-thalamo-cortical circuits that ultimately control motor action. Altogether, these findings compel attention to the potential functional significance of D 1 family receptors both for cognitive processes in normal individuals and for
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the thought fragmentation characteristic of diseases like schizophrenia. Accordingly, we have directed considerable effort to understanding the place of the D 1 receptor in prefrontal circuitry, and in particular, its place in the pyramidal and nonpyramidal neurons that comprise the intrinsic cells of the cerebral cortex.
a second messenger cascade that results in a variety of effects, including enhanced L-type calcium currents w36– 38x, reduction of N- and P-type calcium currents, enhanced NaqrKq ATPase activity w39x, and enhanced NMDA gated currents w40–42x. The interaction between D 1 receptors and glutamatergic inputs is of special interest, given the localization of these receptors adjacent to asymmetric, presumably glutamatergic synapses w43,44x.
4. The D 1 receptor in pyramidal neurons 5. D 1 mechanisms in interneurons A major theme in cortical physiology is that the receptive field of a pyramidal neuron is established by afferent inputs, including its lateral inhibitory input. By extrapolation from estimates made on hippocampal pyramidal cells, the cortical pyramidal neuron can be assumed to integrate literally thousands of afferent inputs and, through its efferent projection, control movement and affect. A full understanding of the functional capacity of even a single pyramidal cell requires knowledge not only of its biophysical properties but its circuitry and signaling mechanisms in vivo. In this context, it is well appreciated that the dopamine axons represent a significant source of afferentation of prefrontal cortex in primates and other animals w26–29x. Further, experimental depletion of dopamine in prefrontal areas of rhesus monkeys has been shown to produce impairments in working memory performance w14x. In pursuit of the anatomical and functional basis of dopamine actions in cortical circuits, we have learned that dopamine axons, originating in brain stem nuclei, form synapses on the shafts and spines of cortical pyramidal neurons w18,19,30x. Moreover, the spines of pyramidal neurons are often the targets of paired dopamine and excitatory terminals, the latter presumed to arise from other cortical or thalamic sources w18x. Synaptic triads, as we have termed these synaptic arrangements, are found in prefrontal, premotor and motor cortex, suggesting that this anatomical architecture may be widespread and common to many cortical areas. We have also studied the distribution of dopamine receptors in prefrontal cortex. We have learned that the D 1 family of dopamine receptors are at least 20-fold more abundant than D 2 family receptors in this area w31,32x. Combined light and ultrastructural analyses have revealed that the distal dendrites and spines of pyramidal cells are the most prominent cellular element labeled by antisera directed against the D 1 receptor w33,34x. This receptor is found in close proximity to putative glutamatergic axon terminals giving rise to asymmetric synapses on the same spine. The functional effect of dopaminergic neurotransmission in cortical circuits is not yet fully understood. In striatal slices, dopamine can both inhibit w35x and excite w36x striatal neurons. Stimulation of D 1 receptors activates
Given the microcircuitry of the prefrontal cortex, it is obvious that interneurons must be as integral to the machinery of cognitive function as are projection neurons. Indeed, recent studies in our laboratory have revealed that interneurons have ‘memory fields’ just as do pyramidal neurons. We have recently discovered that the memory fields of interneurons mirror that of their nearest neighbor pyramidal neurons, i.e., their preferred direction of firing in a spatial task is often very similar to that of an adjacent pyramidal neuron w17x. On the other hand, if the two neurons are at some distance from each other, the relationship tends to be orthogonal w6x. As part of our ongoing effort to elucidate the mechanisms by which D 1 receptor function controls cognitive processing in the prefrontal cortex, we have recently studied the distribution of D 1 receptors in prefrontal interneurons. We have shown that the D 1 receptor is present in GABAergic interneurons and is preferentially found in those subtypes of interneurons which provide the strongest inhibitory input to the perisomatic region of cortical pyramidal cells, the parvalbumin containing basket and chandelier cells w45x. Further, the subcellular localization of the D 1 receptor in interneurons is analogous to that seen in pyramidal cells, i.e., the receptor is located in the distal dendrites of interneurons, adjacent to asymmetric, presumably glutamatergic synapses, as well as in presynaptic axon terminals. The functional effect of D 1 receptors on cortical interneurons is not yet established, but stimulation of D 1 family receptors in the striatum and substantia nigra, increases the synthesis and release of GABA w46–48x.
6. Feedforward inhibition model of dopamine action vis a vis cognitive circuitry We have recently suggested a circuit model to explain the biphasic action of D 1 receptor stimulation on working memory performance w49,50x, and neuronal delay period firing w16x which focuses on the interactions between pyramidal and nonpyramidal neurons. The essence of this model is that D 1 receptor stimulation enhances excitatory inputs to both pyramidal cells and interneurons, but this
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Fig. 3. A model for relationship between D1 receptor stimulation and working memory performance. Dopamine, acting at D1 receptors Žred., enhances glutamatergic inputs to both pyramidal cells Žgray. and interneurons Žblue.. At low levels of dopamine release ŽA., these inputs are not enhanced to either pyramidal neurons or interneurons. At moderate levels of dopamine release, the glutamatergic inputs to pyramidal cells are primarily enhanced leading to an increase in pyramidal cell delay activity and improved working memory function ŽB.. At high levels of dopamine release, the glutamatergic inputs are enhanced to both pyramidal cells and interneurons, leading to a reduction in pyramidal cell activity by feed forward inhibition with resultant impairment of working memory function ŽC.. wFrom 45x.
enhancement is more effective on pyramidal cells. With this arrangement, increasing levels of dopamine stimulation of D 1 receptors will result in enhanced pyramidal cell firing, and with it working memory performance. However at some point, the D 1 effect on pyramidal cells will plateau and further increases in dopamine levels will result mainly in enhancement of interneuron activity. Pyramidal cell delay activity will then be limited by D 1 mediated feedforward inhibition, resulting in impairment of working memory function ŽFig. 3.. Two lines of evidence support the possible differential effectiveness of dopamine at D 1 receptors in pyramidal versus nonpyramidal cells hypothesized above. First, pyramidal cell dendrites have a higher density of close contacts with dopaminergic axon terminals than interneuron dendrites w51x, and thus are in closer proximity to dopamine release sites than interneurons. Second, the D 1 receptor acts via a cascade of diffusable second messengers w52x. On pyramidal neurons, the spine may act as a diffusion barrier to maintain a high concentration of second messengers at the associated excitatory synapse for maximal effect w53,54x. On interneurons, D 1 receptor and asymmetric synapses are located on the dendritic shaft, which would allow for more diffusion of second messengers and thus a reduced effect at the adjacent asymmetric synapse. While this model parsimoniously explains the relationship between D1 receptor stimulation and working memory function, other aspects of the modulatory control of cognitive function have yet to be worked out. In particular, the effect of D 2 action on cognitive processes must be more fully addressed, especially in light of the recent localization of D4 receptors on cortical interneurons w55,56x. In addition, the role of serotonin in modulating cortical function is just beginning to be understood w57x. The more that is learned about the localization of neurotransmitter receptors in the functional circuitry of the prefrontal cortex, the
greater the opportunity to achieve new insight into the complex phenomena relevant to neuropsychiatric disorders.
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w55x L. Mrzljak, C. Bergson, M. Pappy, R. Huff, R. Levenson, P.S. Goldman-Rakic, Localization of dopamine D4 receptors in GABAergic neurons of the primate brain, Nature 381 Ž1996. 245– 248. w56x G.V. Williams, S.G. Rao, P.S. Goldman-Rakic, Effects of dopamine D4 antagonists on mnemonic activity of neurons in primate prefrontal cortex, Society of Biological Psychiatry 5th Annual Convention, Toronto, 1998. w57x G.V. Williams, S.G. Rao, P.S. Goldman-Rakic, Attenuation of memory fields in primate prefrontal cortical pyramidal cell and interneurons by selective 5-HT2 antagonists, Soc. Neurosci. Abstr., Vol. 23 Ž1997. 627.7. w58x L.M. Romanski, P.S. Goldman-Rakic, Physiological identification of an auditory domain in the prefrontal cortex of the awake behaving monkey, Soc. Neurosci. Abstr., Vol. 25 Ž1999. 620.1. w59x G.V. Williams, S.G. Rao, P.S. Goldman-Rakic, The influence of 5-HT3 receptors on local circuit function in primate prefrontal cortex, Soc. Neurosci. Abstr., Vol. 25 Ž1999. 355.13. w60x S.A. Castner, P.S. Goldman-Rakic, Profound cognitive impairments in non-human primates exposed to amphetamine, Soc. Neurosci. Abstr., Vol. 25 Ž1999. 627.6.
Interactive report
D 1 receptors in prefrontal cells and circuits
1
P.S. Goldman-Rakic ) , E.C. Muly, III, G.V. Williams Yale UniÕersity School of Medicine, Neurology Section, P.O. Box 208001r SHM B404, 333 Cedar Street, New HaÕen, CT 06510-8001, USA Accepted 7 August 1999
Keywords: Primate; Non-human primate; Working memory; Conition; Delayed response; Inhibitory; Interneuron; Pyramidal neuron
Contents 1. Introduction .
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2. Dopamine and cognition
3. Dopamine modulation of mnemonic function in prefrontal neurons .
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4. The D1 receptor in pyramidal neurons 5. D1 mechanisms in interneurons
6. Feedforward inhibition model of dopamine action vis a vis cognitive circuitry . References
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1. Introduction A worthy goal of systems neuroscience is to dissect the cellular and circuit basis of behavior in order to extend the insights gained from the study of normal brain organization in animal models to an understanding of a clinical disorder. We have been employing this strategy to elucidate the organic basis of the cardinal symptoms of schizophrenia, including the thought process in this disorder. Our studies are based on the hypothesis that many features of schizophrenia represent a failure in the neural mechanisms by which prefrontal cortex stores and processes information in working memory w1,2x. From the broadest perspective, working memory is a system of operations for processing information in real time, i.e., on a moment to moment basis, and even subtle deficiencies in the machinery of working memory can mean substantial ) Corresponding author. Tel.: q1-203-785-4808; Fax: q1-203-7855263; E-mail: [email protected] 1 Published on the World Wide Web on 9 November 1999.
deficits in ideation, reasoning and planning such as are observed in psychosis w2x. Disturbances in the finely tuned mechanisms of temporal integration that are essential to working memory may also be at the core of impairments which are less obviously cognitive, such as smooth pursuit eye tracking and pre-pulse inhibition. In the past decade, major advances have been made in our capacity to decipher the elemental basis of working memory processes as they operate in the prefrontal cortex of macaque monkeys. We and others have been able to characterize the functional properties of prefrontal neurons as they are specialized for particular operations in working memory such as encoding a specific stimulus, maintaining it ‘on line’ and directing an appropriate memory-guided response. These studies have shown that prefrontal neurons are remarkably content specific, i.e., individual neurons encode and transiently store specific items of information, such as the location of an object w3,4x, the direction of a prior response w5x, the identity of objects or faces w6,7x and the identity of voices and sounds w58x. These prefrontal neurons and the mechanisms which endow them with the
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capacity to represent a stimulus in its absence, have become a major focus of our interest. In this chapter, we describe our efforts to understand the pyramidal and nonpyramidal cells of the prefrontal cortex, the area of the brain most associated with the working memory functions of the brain. We also address the circuit and receptor mechanisms which regulate pyramidal and nonpyramidal cell excitability in vivo. Specifically, we review our studies on the dopamine modulation of working memory circuits. This work may seem far afield from the clinical disorder of schizophrenia, but we hope to demonstrate that a connection may exist between the disposition of neurotransmitter receptors in individual neurons and behavioral symptoms, and that such a connection may illuminate the biological basis of this disease.
ies, the anatomical precision of immunohistochemistry and in situ hybridization and not least, the development of sophisticated behavioral paradigms, are among the major advances that have made understanding dopamine’s role in cognition a reasonable goal. All of these approaches have been applied to the analysis of the anatomical and functional architecture of the dopaminergic innervation of the prefrontal cortex in our laboratory. As the micro-columnar architecture of prefrontal cortex is repeated in most other regions of the cerebral cortex, the mechanisms elucidated in this area have a high likelihood of revealing general principles of dopamine modulation applicable to other cortical areas.
3. Dopamine modulation of mnemonic function in prefrontal neurons 2. Dopamine and cognition Cognitive symptoms have been associated with dopamine dysregulation in numerous diseases including Huntington’s disease w8x, schizophrenia w9x, depression w10x, drug addiction w11x, and Parkinson’s Disease w12x as well as in normal aging w13x. This neurotransmitter has been linked to a wide variety of functions including motivation, reward, affect and movement, all of which could affect performance on cognitive tasks without affecting the brain’s information processing systems per se. Nevertheless, a variety of studies in experimental animals along with a plethora of neuropsychological studies in clinical populations suggest a direct association between altered dopamine transmission in the prefrontal cortex and cognitive deficits w14,15x. The cloning of five distinct dopamine receptors, the development of receptor-specific ligands and antibod-
The cellular basis of receptive field properties is among the most challenging issues in the study of higher cortical function. To date, neurotransmitter-specific actions on cortical neurons have been confined largely to examination of in vitro systems. Now, very recently, we have developed the methods to analyze the pharmacological actions of drugs on neurons as they are engaged in cognitive processes in awake behaving animals. With this method we have shown that the ‘memory fields’ of prefrontal cortex are modulated by neurotransmitters such as dopamine w16x, serotonin w59x, and the inhibitory neurotransmitter, gamma-amino-butyric acid ŽGABA. in distinctively different ways w17x. This is significant not only because they reveal the endogenous modulators of cognition on normal processes but also because dysfunction in dopamine, serotonergic, andror GABAergic neurotransmission has been
Fig. 1. Dose-dependent effects of the selective D1 antagonist SCH 39166 on activity of a prefrontal neuron. Top: Control recording showing significant delay period activity Žfor the preferred target direction of 08.. Middle: SCH 39166 Ž25 nA. induces dramatic enhancement of delay activity selectively, without any increase in the background activity of the cell. Bottom: At a high dose Ž75 nA., SCH 39166 abolishes activity during the delay period as well as other periods of the task. Note: C s cue period Ž0.5s., D s delay period Ž3.0s., R s response period Žbin s 50 ms.. Drug used at 10 mM, pH 3.5–4.0. wFrom 16x.
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implicated in many disorders of cognition. We have begun to study the actions of these neurotransmitters with respect to the localization of the relevant receptors within the cortical micro-architecture. In particular, we have shown that D 1 receptors can modulate excitatory transmission in neurons which are involved directly in the mnemonic component of the task ŽFig. 1. w59x. The spatial tuning of prefrontal neurons engaged in spatial working memory is enhanced at moderate levels of D 1 occupancy and reduced at both lower and higher levels of occupancy. The specificity of drug action on single cell activity may be accounted for by the specific synaptic arrangement of D 1 receptors in spines that receive excitatory inputs, presumably from the visual pathways carrying highly processed visuospatial information w18,19x. These findings may be relevant to clinical conditions. It is of interest that a recent PET study has revealed that the D 1 receptor is decreased in the prefrontal cortex of both medicated and non-medicated schizophrenic patients. In addition, the density of D 1 receptors was positively correlated with performance of the patients on the Wisconsin Card Sort Task w20x. Normal aging also brings with it a decline in dopamine levels and D1 receptor function w21– 23x and in working memory w13,24x. Given the vulnerability of cognitive functions to dopamine dysfunction, it would not be surprising if a common pathophysiological process were responsible for the cognitive deficits in Parkinson’s disease, aged individuals and schizophrenic patients. In our model, as illustrated in Fig. 2, there is an optimal level of D 1 receptor occupancy for efficient physiological signaling and optimal performance. This raises the possibility that neuroleptic resistance of both negative symptoms and cognitive dysfunction in schizophrenic patients may be related to an abnormality of D 1 function. Support
Fig. 2. Diagram illustrating the biphasic modulation of working memory function by dopamine was revealed in 16x. At extremely low levels of dopamine and D1 receptor activation, as might occur in Parkinson’s disease, there would be no dopaminergic facilitation of functional glutamatergic inputs to prefrontal neurons. The consequent absence of memory fields, as indicated by the effects of high levels of D1 antagonists in iontophoretic studies, should result in loss of working memory. In this condition, D1 agonists should be capable of reinstating memory fields. As dopamine levels rise they enter a normal range in which there is an optimum level of D1 receptor activation for the generation of memory fields. A high level of motivation was required to perform the ODR task which would account for dopamine levels being near the high end of the range and for the improvement of memory fields by low levels of D1 antagonists. If dopamine levels rise further, beyond this range, due to severe stress or acute amphetamine administration, then D1 receptor activation produces an increasing level of inhibition of selective glutamatergic inputs to prefrontal cells. This should lead to dissipation of memory fields, as suggested by the effects of iontophoresis of D1 agonists in the present study, and a subsequent loss of working memory. In this opposite extreme the memory fields should be reinstated by D1 antagonists. wFrom 25x.
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for this possibility is provided by two recent findings from this laboratory: D 1 message and protein in the prefrontal cortex of rhesus monkeys is down-regulated by chronic neuroleptic treatment w25x; and the same treatment that lowers the level of D 1 receptors produces impairments in working memory performance w60x. We conclude from these and other observations that cortical dopamine regulates cognitive processing via its action at D 1 receptors. This may translate to a dampening and disruption of information flow in the cortico-striato-tectal and corticostriato-thalamo-cortical circuits that ultimately control motor action. Altogether, these findings compel attention to the potential functional significance of D 1 family receptors both for cognitive processes in normal individuals and for
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the thought fragmentation characteristic of diseases like schizophrenia. Accordingly, we have directed considerable effort to understanding the place of the D 1 receptor in prefrontal circuitry, and in particular, its place in the pyramidal and nonpyramidal neurons that comprise the intrinsic cells of the cerebral cortex.
a second messenger cascade that results in a variety of effects, including enhanced L-type calcium currents w36– 38x, reduction of N- and P-type calcium currents, enhanced NaqrKq ATPase activity w39x, and enhanced NMDA gated currents w40–42x. The interaction between D 1 receptors and glutamatergic inputs is of special interest, given the localization of these receptors adjacent to asymmetric, presumably glutamatergic synapses w43,44x.
4. The D 1 receptor in pyramidal neurons 5. D 1 mechanisms in interneurons A major theme in cortical physiology is that the receptive field of a pyramidal neuron is established by afferent inputs, including its lateral inhibitory input. By extrapolation from estimates made on hippocampal pyramidal cells, the cortical pyramidal neuron can be assumed to integrate literally thousands of afferent inputs and, through its efferent projection, control movement and affect. A full understanding of the functional capacity of even a single pyramidal cell requires knowledge not only of its biophysical properties but its circuitry and signaling mechanisms in vivo. In this context, it is well appreciated that the dopamine axons represent a significant source of afferentation of prefrontal cortex in primates and other animals w26–29x. Further, experimental depletion of dopamine in prefrontal areas of rhesus monkeys has been shown to produce impairments in working memory performance w14x. In pursuit of the anatomical and functional basis of dopamine actions in cortical circuits, we have learned that dopamine axons, originating in brain stem nuclei, form synapses on the shafts and spines of cortical pyramidal neurons w18,19,30x. Moreover, the spines of pyramidal neurons are often the targets of paired dopamine and excitatory terminals, the latter presumed to arise from other cortical or thalamic sources w18x. Synaptic triads, as we have termed these synaptic arrangements, are found in prefrontal, premotor and motor cortex, suggesting that this anatomical architecture may be widespread and common to many cortical areas. We have also studied the distribution of dopamine receptors in prefrontal cortex. We have learned that the D 1 family of dopamine receptors are at least 20-fold more abundant than D 2 family receptors in this area w31,32x. Combined light and ultrastructural analyses have revealed that the distal dendrites and spines of pyramidal cells are the most prominent cellular element labeled by antisera directed against the D 1 receptor w33,34x. This receptor is found in close proximity to putative glutamatergic axon terminals giving rise to asymmetric synapses on the same spine. The functional effect of dopaminergic neurotransmission in cortical circuits is not yet fully understood. In striatal slices, dopamine can both inhibit w35x and excite w36x striatal neurons. Stimulation of D 1 receptors activates
Given the microcircuitry of the prefrontal cortex, it is obvious that interneurons must be as integral to the machinery of cognitive function as are projection neurons. Indeed, recent studies in our laboratory have revealed that interneurons have ‘memory fields’ just as do pyramidal neurons. We have recently discovered that the memory fields of interneurons mirror that of their nearest neighbor pyramidal neurons, i.e., their preferred direction of firing in a spatial task is often very similar to that of an adjacent pyramidal neuron w17x. On the other hand, if the two neurons are at some distance from each other, the relationship tends to be orthogonal w6x. As part of our ongoing effort to elucidate the mechanisms by which D 1 receptor function controls cognitive processing in the prefrontal cortex, we have recently studied the distribution of D 1 receptors in prefrontal interneurons. We have shown that the D 1 receptor is present in GABAergic interneurons and is preferentially found in those subtypes of interneurons which provide the strongest inhibitory input to the perisomatic region of cortical pyramidal cells, the parvalbumin containing basket and chandelier cells w45x. Further, the subcellular localization of the D 1 receptor in interneurons is analogous to that seen in pyramidal cells, i.e., the receptor is located in the distal dendrites of interneurons, adjacent to asymmetric, presumably glutamatergic synapses, as well as in presynaptic axon terminals. The functional effect of D 1 receptors on cortical interneurons is not yet established, but stimulation of D 1 family receptors in the striatum and substantia nigra, increases the synthesis and release of GABA w46–48x.
6. Feedforward inhibition model of dopamine action vis a vis cognitive circuitry We have recently suggested a circuit model to explain the biphasic action of D 1 receptor stimulation on working memory performance w49,50x, and neuronal delay period firing w16x which focuses on the interactions between pyramidal and nonpyramidal neurons. The essence of this model is that D 1 receptor stimulation enhances excitatory inputs to both pyramidal cells and interneurons, but this
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Fig. 3. A model for relationship between D1 receptor stimulation and working memory performance. Dopamine, acting at D1 receptors Žred., enhances glutamatergic inputs to both pyramidal cells Žgray. and interneurons Žblue.. At low levels of dopamine release ŽA., these inputs are not enhanced to either pyramidal neurons or interneurons. At moderate levels of dopamine release, the glutamatergic inputs to pyramidal cells are primarily enhanced leading to an increase in pyramidal cell delay activity and improved working memory function ŽB.. At high levels of dopamine release, the glutamatergic inputs are enhanced to both pyramidal cells and interneurons, leading to a reduction in pyramidal cell activity by feed forward inhibition with resultant impairment of working memory function ŽC.. wFrom 45x.
enhancement is more effective on pyramidal cells. With this arrangement, increasing levels of dopamine stimulation of D 1 receptors will result in enhanced pyramidal cell firing, and with it working memory performance. However at some point, the D 1 effect on pyramidal cells will plateau and further increases in dopamine levels will result mainly in enhancement of interneuron activity. Pyramidal cell delay activity will then be limited by D 1 mediated feedforward inhibition, resulting in impairment of working memory function ŽFig. 3.. Two lines of evidence support the possible differential effectiveness of dopamine at D 1 receptors in pyramidal versus nonpyramidal cells hypothesized above. First, pyramidal cell dendrites have a higher density of close contacts with dopaminergic axon terminals than interneuron dendrites w51x, and thus are in closer proximity to dopamine release sites than interneurons. Second, the D 1 receptor acts via a cascade of diffusable second messengers w52x. On pyramidal neurons, the spine may act as a diffusion barrier to maintain a high concentration of second messengers at the associated excitatory synapse for maximal effect w53,54x. On interneurons, D 1 receptor and asymmetric synapses are located on the dendritic shaft, which would allow for more diffusion of second messengers and thus a reduced effect at the adjacent asymmetric synapse. While this model parsimoniously explains the relationship between D1 receptor stimulation and working memory function, other aspects of the modulatory control of cognitive function have yet to be worked out. In particular, the effect of D 2 action on cognitive processes must be more fully addressed, especially in light of the recent localization of D4 receptors on cortical interneurons w55,56x. In addition, the role of serotonin in modulating cortical function is just beginning to be understood w57x. The more that is learned about the localization of neurotransmitter receptors in the functional circuitry of the prefrontal cortex, the
greater the opportunity to achieve new insight into the complex phenomena relevant to neuropsychiatric disorders.
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