What is this article about?

A goal of systems neuroscience is to dissect the cellular and circuit basis of behavior in order to complement the insights from studies on normal brain organization in animal models to an understanding of a clinical disorder.

For example, by using this strategy, the organic basis of schizophrenia are elucidated. Many features of schizophrenia represent a failure in the neural mechanisms by which prefrontal cortex stores and processes information in working memory. In this paper, the authors describe the pyramidal and non-pyramidal cells of the prefrontal cortex. The prefrontal cortex is the area of the brain which is most associated with the working memory functions of the brain. They also review their study on dopamine modulation of working memory circuits. The authors want to describe how there is a connection between the disposition of neural transmitter receptors in individual neurons and behavioral symptoms.

What is there to say about dopamine and cognition?

Huntington’s disease, schizophrenia, depression, drug addiction and Parkinson’s disease are all associated with dysregulations in dopamine systems. Dopamine is linked to motivation, reward, affect and movement, and these can all affect performance on cognitive tasks, without affecting the brain’s information processing systems per se. Studies show that there is a direct association between altered dopamine transmission in the prefrontal cortex and cognitive deficits. The cloning of five distinct dopamine receptors, the development of receptor-specific ligands and antibodies, the anatomical precision of immunohistochemistry and in situ hybridization, and the development of sophisticated behavioral paradigms are a few of the major advances that have made understanding dopamine’s role in cognition a reasonable goal.

What about dopamine modulation of mnemonic function in pre-frontal neurons?

In the study of higher cortical function, the cellular basis of receptive field properties is one of the most challenging issues. Previously, neurotransmitter-specific actions on cortical neurons have been studies using in vitro systems. Nowadays, there are methods developed to analyze the pharmacological actions of drugs on neurons as they are engaged in cognitive processes in awake behaving animals. Using this method the researchers showed that the ‘memory fields’ of prefrontal cortex are modulated by neurotransmitters such as dopamine, serotonin, and GABA. The researchers looked at the actions of these neurotransmitters with respect to the localization of the relevant receptors within the cortical micro-architecture. They showed that D1 receptors can modulate excitatory transmission in neurons which are involved in the mnemonic component of the task. At moderate levels of D1 occupancy, the spatial tuning of prefrontal neurons is enhanced. At higher levels of D1 occupancy, this is reduced.

In clinical conditions, this is an important finding. A PET study has shown that the D1 receptor is decreased in the prefrontal cortex of both medicated and non-medicated schizophrenic patients. The density of D1 receptors are positively correlated with performance of the patients on the Wisconsin Card Sort Task. Aging also leads to a decline in dopamine levels and in D1 receptor function and in working memory.

In schizophrenic patients, both the negative symptoms and cognitive dysfunctions may be related to abnormal D1 functioning. These findings signal the need for attention the importance of D1 family receptors for both cognitive processes in normal individuals and for the symptoms of schizophrenia.

What about the D1 receptor in pyramidal neurons?

The receptive field of a pyramidal neuron is established by afferent inputs, such as its lateral inhibitory input. The cortical pyramidal neuron can be assumed to integrate thousands of afferent inputs and control movement and affect through efferent projection. In rhesus monkeys, depletion of dopamine has been shown to produce impairments in working memory performance. It has also been shown that the D1 family of dopamine receptors are 20-fold more abundant than D2 family receptors in the prefrontal cortex. However, the functional effect of dopaminergic neurotransmitters in cortical circuits is not yet fully understood. In striatal slices, dopamine can both inhibit and excite striatal neurons. Stimulation of D1 receptors activates a second messenger cascade that results in a variety of effects, such as enhanced L-type calcium currents, reduction of N- and P-type calcium currents, enhances NA+/K+ ATPase activity, and enhanced NMDA gated currents. The interaction between D1 receptors and glutamergic inputs is of special interest, because the localization of these receptors are adjacent to asymmetric.

What about D1 mechanisms in interneurons?

Interneurons must be as integral to the machinery of cognitive function as are projection neurons. Interneurons have been shown to have ‘memory fields’, similar to pyramidal neurons. The memory fields of interneurons mirror that of their highest pyramidal neurons: their preferred direction of firing in a spatial task if often very similar to that of their nearest neighbour pyramidal neurons. The authors studied the distribution of D1 receptors in prefrontal interneurons. They showed that the D1 receptor is present in GABAergic interneurons and is 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. The subcellular localization of the D1 receptor in interneurons is analogous to that seen in pyramidal cells: the receptor is located in the distal dendrites of interneurons, adjacent to asymmetric, presumably glutamergic synapses, as well as in presynaptic axon terminals. The functional effects of D1 receptors on cortical interneurons is not yet established, but stimulation of D1 family receptors in the stratium and substantia nigra have been shown to increase the synthesis and also the release of GABA.

What about the feedforward inhibition model of dopamine action versus cognitive circuitry?

The essence of the feedforward inhibition model is that D1 receptor stimulation enhances excitatory inputs to both pyramidal cells and interneurons, but this enhancement is more effective on pyramidal cells. Increasing levels of dopamine stimulation of D1 receptors will result in enhanced pyramidal cell firing, and enhanced working memory performance. However, at some point, the D1 effect on pyramidal cells will plateau and further increases in dopamine levels will result in enhancement of interneuron activity. Then, pyramidal cell delay activity will be limited by D1 mediated feedforward inhibition, resulting in impairment of working memory function.

There are two types of evidence for possible differential effectiveness of dopamine at D1 receptors in pyramidal versus nonpyramidal cells. First, pyramidal cell dendrites have a higher density of close contacts with dopaminergic axon terminals than interneuron dendrites, and are therefore in closer proximity to dopamine release sites than interneurons. Second, D1 receptor acts via as cascade of diffusible second messengers. 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. On interneurons, D1 receptor and asymmetric synapses are located on the dendritic shaft, which allows for more diffusion of second messengers and leads to a reduced effect at the adjacent asymmetric synapse. This model thus explains the relationship between D1 receptor stimulation and working memory, but other aspects of the modulatory control of cognitive function have not been studied yet,.