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Priming the LTP Pump—Dopamine Delivers in Prefrontal Cortex

16 May 2006. Though dopamine has been linked in various ways to schizophrenia, it is still unclear what pathological role, if any, this neurotransmitter plays in the disease. One possible hint may be found in the May 3 Journal of Neuroscience. Satoru Otani and colleagues at the Pierre and Marie Curie branch of the University of Paris, France, report that background or tonic levels of dopamine help regulate synaptic plasticity in rat prefrontal cortex (PFC), an area of the brain that is intimately involved in executive function in humans, and has been linked to suboptimal decision-making and thought processes in schizophrenia patients.

Otani and colleagues set out to answer a key question that has puzzled neuroscientists for some time: What role does tonic dopaminergic activity play in the cortex? While fast, phasic transmission from midbrain dopaminergic neurons has been associated with modulation of neural circuits through long-term potentiation (LTP), mechanisms to explain the effect of tonic dopamine have not been as forthcoming, despite the fact that background dopamine seems just as important for executive function (see Schultz, 2002). Now, first author Yoshiki Matsuda and colleagues show that tonic dopamine can have a profound effect on layer V pyramidal neurons in the PFC of rats. While repeated, or “tetanic,” stimulation of these cells in slice preparations elicits long-term depression (LTD), a phenomenon that makes neurons less sensitive to further stimulation, Matsuda and colleagues have found that tetanic stimuli have the opposite effect—inducing LTP—if the cells have first been “primed” with dopamine.

The priming in this experimental setting comes from bathing PFC slices with the neurotransmitter to mimic normal dopaminergic input. Matsuda found that steeping the slices in the dopamine (100 μMolar) for 12.5 minutes 40 minutes before electrically stimulating layers I-II and adding more dopamine was sufficient to convert LTD to LTP in the pyramidal layer (the second application of dopamine was essential for the effect). While the 100 μM seems relatively high, the authors could achieve the same result by continuously applying only 3 μM dopamine prior to the paired electrical/dopamine stimulation.

To investigate the mechanism behind this plasticity, Matsuda and colleagues tested which neuron receptors are required for the LTD-to-LTP conversion. They found that both D1 and D2 dopamine receptors need to be stimulated in order for the LTP pump to be primed. They also found that the N-methyl-D-aspartate form of glutamate receptor plays a role, though the involvement of these receptors seems more complex. When NMDA receptors were blocked with the antagonist AP-5 prior to priming, then only LTD was elicited by the tetanic stimuli/dopamine treatment. On the other hand, if AP-5 was added during the electrical/dopaminergic stimulus, or “induction” phase, then about half the neurons exhibited LTP and the remainder LTD. This suggests that there may be subpopulations of pyramidal neurons that require NMDA receptor activation for both priming and induction, but others that only require the receptors for priming. Matsuda and colleagues found that metabotrobic glutamate receptors (mGluRs) are also required for tonic dopamine-elicited LTP, though whether mGluRs are specifically needed for priming or induction is unclear—the authors could not determine if the antagonist used washes out of the slices before the induction with tetanic stimuli/dopamine.

Matsuda and coworkers suggest that this dopamine priming effect may explain why LTP can be easily induced in intact PFC, where basal levels of dopamine are maintained by dopaminergic afferent neurons (see, e.g., Takahata and Moghaddam, 2000). And while more work will have to be done to determine if LTD-to-LTP conversion at the behest of tonic dopamine is related in any way to the pathology of schizophrenia, the authors do raise some interesting correlates. For example, about 4 hours elapsed between dissection of the rat PFC slices and the experiments, suggesting that any priming triggered by tonic dopamine must fade during that time. And while this is not representative of what would happen in vivo, the authors note that reduced dopamine levels have been observed in schizophrenia patients (see Akil et al., 1999). Though reduced dopamine receptor levels (see Okubo et al., 1997), which probably reflect down-regulation in response to dopamine excess, have also been observed, “another study (Abi-Dargham et al., 2002) suggested increased levels of dopamine receptors (D1-Rs) in the PFC which may have resulted from the reduced dopaminergic transmission,” suggested Otani via e-mail. It is also worth noting that most antipsychotic drugs are dopaminergic antagonists, but these drugs do not significantly ameliorate PFC-related cognitive effects.

Further bolstering the connection between tonic dopamine and LTP, NMDA receptor dysfunction has also been reported in schizophrenia patients (see Sokolov, 1988). All of these observations tempt the authors to suggest that “a pathological conversion of LTP to LTD may occur in the PFC when the level of basal stimulation of dopamine and NMDA receptors is low.” They suggest that such an abnormal conversion could impair context-dependent selection of action repertories, cognitive components necessary for the realization of goal-directed behavior. In other words, the failure to convert the LTD to LTP could help explain part of the psychopathology of schizophrenia. Of course, whether similar, tonic dopamine-driven LTD-to-LTP conversion occurs in humans remains to be determined.—Tom Fagan.

Matsuda Y, Marzo A, Otani S. The presence of background dopamine signal converts long-term synaptic depression to potentiation in rat prefrontal cortex. Journal of Neuroscience. May 3, 2006;26:4803-4810. Abstract

Comments on News and Primary Papers
Comment by:  Andreas Meyer-Lindenberg
Submitted 15 May 2006 Posted 15 May 2006
  I recommend the Primary Papers

I think this is an interesting paper, as it shows that alterations in tonic dopaminergic stimulation can result in a pronounced and qualitative switch (LTD to LTP) in the behavior of prefrontal neurons. Although the concept of tonic versus phasic dopaminergic stimulation has been adopted widely by the schizophrenia research community, the majority of the preclinical work has focused on acute changes in dopamine concentration and on subcortical structures, especially the nucleus accumbens, and from my perspective as a clinical researcher, it is welcome to see some data that extend to prefrontal cortex and longer timescales, although it must be emphasized that this paper concerns results from rats, in slices in vitro, using tetanic stimulation, and that the pretreatment with dopamine lasted for 40 minutes only. With these caveats, it is exciting to see that pretreatment with dopamine after what the authors presume is a 4-hour period of neurotransmitter depletion during slice preparation produces LTP after a weak tetanic stimulus, compared to LTD that the same stimulus evoked...  Read more

View all comments by Andreas Meyer-Lindenberg

Comment by:  Patricia Estani
Submitted 3 June 2006 Posted 3 June 2006
  I recommend the Primary Papers

Comment by:  Terry Goldberg
Submitted 20 June 2006 Posted 20 June 2006

Matsuda et al. demonstrate that priming D1 and D2 receptors may induce LTP; otherwise, LTD develops. To elaborate, a weak tetanic stimulation and dopamine stimulation produces LTD. However, if dopamine is perfused for 12 to 40 minutes at D1 and D2 receptors and a tetanic stimulus is provided, LTP, a form of cellular learning associated with memory, develops. This study has potentially important implications for understanding the cause of prefrontally based failures in information processing in schizophrenia. It gives additional weight to arguments that reduced dopaminergic tone at the cortical level is responsible for at least some of the cognitive problems associated with the disorder.

It also helps make sense out of some otherwise anomalous data in the literature. For instance, in manipulations of several tests of purported attentional control and vigilance problems, findings appeared more consistent with difficulties in constructing a representation than with attention per se in target detection (e.g.,   Read more

View all comments by Terry Goldberg

Comment by:  Satoru Otani
Submitted 22 July 2006 Posted 24 July 2006

In his June 20 comment, Dr. Goldberg raised an important question concerning our paper: how our results, showing the necessity of D1+D2 receptor coactivation for prefrontal LTP induction and priming, fit into the scheme proposed by Seamans et al., 2001, that is, the differential roles played by D1 and D2 receptors for prefrontal cortex (PFC) cognitive processes.

I think I have to first point out that the dependency of PFC long-term potentiation (LTP) induction (let alone "priming" now) on DA receptor subtypes may vary among subpopulations of PFC synapses. In ventral hippocampus (HC)-PFC synapses, LTP induction requires D1 but not D2 receptors (Gurden et al., 2000). This in vivo study fits with the idea that HC-PFC projection and its D1 receptor-mediated modulation are critical in spatial information processing (working memory) and encoding of this information. However, recent in vivo results of Yukiori Goto at the...  Read more

View all comments by Satoru Otani

Comment by:  Jeremy Seamans
Submitted 26 July 2006 Posted 27 July 2006

Drs. Goldberg and Otani raise some excellent points in their comments on the Matsuda et al. paper. As Dr. Otani alluded to in his latest comment, it is useful to define exactly what is being modulated under different experimental conditions and how this all relates to prefrontal cortex (PFC) function in general.

Dr Otani’s studies investigate synaptic plasticity induced by tetanic stimulation and how this process is modulated by tonic dopamine (DA). Long-term potentiation/long-term depression (LTP/LTD) induced by tetanic stimulation has provided us with perhaps the best model of the cellular basis of long-term memory and has been proposed to underlie, among other things, various aspects of long-term spatial memory and declarative memory. LTP is a long-lasting, passive, associational memory mechanism, unlike working memory that is transient in nature, relies on active processing and is not associational. Therefore, in PFC, it would be highly unlikely that LTP/LTD is the neural mechanism of working memory. However, to solve a working memory problem, one must manipulate...  Read more

View all comments by Jeremy Seamans
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