Dopamine: a potential substrate for synaptic plasticity and memory mechanisms (original) (raw)
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Dopaminergic Influence Over Hippocampal Synaptic Plasticity and Function
Clinical and Experimental Pharmacology, 2012
The hippocampal formation is an important center for spatial and episodic memories. In the most simplified terms, multi-sensory information from the entorhinal cortex enters the dentate gyrus and begins a trisynaptic loop through the CA3 subfield and then to the CA1 subfield of the hippocampus. While the neuronal connections involved are primarily excitatory and inhibitory, there is neuromodulatory innervation of the hippocampus arising from cholinergic and noradrenergic centers. The medial septum provides cholinergic and GABAergic input to the hippocampus, and the consensus is that this regulates theta oscillations that contribute to mechanisms of both plasticity and memory . It has also been demonstrated that the locus coerulus provides a second source of neuromodulation via noradrenergic afferents to the hippocampus [2]. The most common anatomical marker for both norepinephrine and dopamine (DA) synthesis is Tyrosine Hydroxylase (TH), which does not distinguish between the two neurotransmitters. Thus, there is not a clear consensus regarding the extent of direct dopaminergic (DA) innervation from the Ventral Tegmental Area (VTA). Several lines of evidence suggest that DA neurotransmission influences hippocampal plasticity and function , but some recent work questions whether these effects arise from direct dopaminergic afferents or from co-release of DA from noradrenergic fibers within the hippocampus [6]. Here we will discuss the discrepancy arising from several different approaches, and how two viable hypotheses of dopaminergic influence over hippocampal function have arisen.
Dopaminergic control of synaptic plasticity in the dorsal striatum
European Journal of Neuroscience, 2001
Cortical glutamatergic and nigral dopaminergic afferents impinge on projection spiny neurons of the striatum, providing the most signi®cant inputs to this structure. Isolated activation of glutamate or dopamine (DA) receptors produces short-term effects on striatal neurons, whereas the combined stimulation of both glutamate and DA receptors is able to induce long-lasting modi®cations of synaptic excitability. Repetitive stimulation of corticostriatal ®bres causes a massive release of both glutamate and DA in the striatum and, depending on the glutamate receptor subtype preferentially activated, produces either long-term depression (LTD) or long-term potentiation (LTP) of excitatory synaptic transmission. D1-like and D2-like DA receptors interact synergistically to allow LTD formation, while they operate in opposition during the induction phase of LTP. Corticostriatal synaptic plasticity is severely impaired after chronic DA denervation and requires the stimulation of DARPP-32, a small protein expressed in dopaminoceptive spiny neurons which acts as a potent inhibitor of protein phosphatase-1. In addition, the formation of LTD and LTP requires the activation of PKG and PKA, respectively, in striatal projection neurons. These kinases appear to be stimulated by the activation of D1-like receptors in distinct neuronal populations.
Dopaminergic Modulation of Long-term Synaptic Plasticity in Rat Prefrontal Neurons
Cerebral Cortex, 2003
In rat prefrontal cortex (the prelimbic area of medial frontal cortex), the induction of long-term depression (LTD) and long-term potentiation (LTP) of glutamatergic synapses is powerfully modulated by dopamine. The presence of dopamine in the bathing medium facilitates LTD in slice preparations, whereas in the anesthetized intact brain, dopamine released from dopaminergic axon terminals in the prefrontal cortex facilitates LTP. Dopaminergic facilitation of LTD is at least partly achieved by postsynaptic biochemical mechanisms in which enzymatic processes triggered by dopamine receptor activation cooperate with those triggered by glutamate metabotropic receptor activation. Evidence suggests that dopamine facilitates LTP also in the slice condition. In this case, dopamine receptors must be pre-stimulated ('primed') before the application of high-frequency stimuli in the presence of dopamine. This procedure may mimic baseline stimulation of dopamine receptors that occurs under physiological conditions.
Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control
Cells, 2021
Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical and subcortical areas. Finally, we will delineate how the effect of DA on dendritic spines places...
Role of Adenosine in the Control of Homosynaptic Plasticity in Striatal Excitatory Synapses
Journal of Integrative Neuroscience, 2005
Long-lasting, activity-dependent changes in synaptic efficacy at excitatory synapses are critical for experience-dependent synaptic plasticity. Synaptic plasticity at excitatory synapses is determined both presynaptically by changes in the probability of neurotransmitter release, and postsynaptically by changes in the availability of functional postsynaptic glutamate receptors. Two kinds of synaptic plasticity have been described. In homosynaptic or Hebbian plasticity, the events responsible for synaptic strengthening occur at the same synapse as is being strengthened. Homosynaptic plasticity is activitydependent and associative, because it associates the firing of a postsynaptic neuron with that of the presynaptic neuron. Heterosynaptic plasticity, on the other hand, is activityindependent and the synaptic strength is modified as a result of the firing of a third, modulatory neuron. It has been suggested that long-term changes in synaptic strength, which are associated with gene transcription, can only be induced with the involvement of heterosynaptic plasticity. The neuromodulator adenosine plays an elaborated pre-and postsynaptic control of glutamatergic neurotransmission. This paper reviews the evidence suggesting that in some striatal excitatory synapses, adenosine can provide the heterosynaptic-like * Corresponding author.
Scientific reports, 2017
Long-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP. This effect was dependent on protein synthesis, activation of NMDA-receptors and CaMKII. We also show that GABAA-receptor mediated mechanisms are involved in the enhancement of late-LTP. We could show that short-term plasticity and baseline synaptic transmission were unaffected by D4R inhibition. On the other hand, antagonizing D4R prevented both early and late forms of LTD, showing that activation of D4Rs triggered a dual function. Synap...
Dopaminergic modulation of the persistence of one-trial hippocampus-dependent memory
Learning & Memory, 2006
The persistence of new memory traces in the hippocampus, encoded following appropriate activation of glutamatergic receptors and the induction of synaptic plasticity, can be influenced by heterosynaptic activation of neuromodulatory brain systems. We therefore investigated the effects of a hippocampus-specific blockade of dopamine D1/D5 receptors on the persistence of spatial memory encoded in one trial using a delayed matching-to-place (DMP) task in a watermaze in which rats learn a new escape location each day. A within-subjects design was used such that both short (20 min) and long (6 h) retention intervals, and both drug (SCH23390, a D1/D5 receptor antagonist) and vehicle (aCSF) infusions were tested on different days in the same animals. Bilateral intrahippocampal infusion of SCH23390 (5 µg in 1 µL per side) prior to trial 1 (encoding) caused a differential impairment as a function of memory delay-with no effect during trial 2 (memory retrieval) after a 20-min interval, but a block of memory at 6 h. Further experiments revealed that infusion of SCH23390 immediately after trial 1 had no effect on retention 6 h later, and the poor memory seen at long retention intervals when the drug was present at encoding was not due to a state-dependent failure of retrieval. These results suggest that activation of D1/D5 receptors during memory encoding is necessary for the formation of a persistent memory trace in the hippocampus. The complementary effects of D1/D5 receptor blockade on the persistence of LTP and the duration of memory are consistent with the idea that changes in synaptic strength underlie memory. 4 Present address: Roche Palo Alto LLC, Palo Alto, California 94304, USA. 5 Corresponding author. E-mail r.g.m.morris@ed.ac.uk; fax 44-131-650-4579. Article is online at
Differentiative Effects of Dopamine on Striatal Neurons Involve Stimulation of the cAMP/PKA Pathway
Molecular and Cellular Neuroscience, 1998
The neurotransmitter dopamine (DA) stimulates neurite outgrowth and growth cone formation in cultures of embryonic rat striatum through activation of D 1 but not D 2 receptors. We show here that neurite outgrowth could be stimulated to a similar extent by elevating cellular cAMP levels. Second, the neuritotrophic effect of DA was completely abolished by inhibiting adenylate cyclase or protein kinase A (PKA) but not protein kinase C (PKC). Third, double staining of cultures with antibodies against growthassociated protein-43 (GAP-43) and the phosphorylated form of the cAMP response element binding protein (pCREB) showed that pCREB was nearly exclusively associated with GAP-43-positive, i.e., actively growing, neurons. Again, this effect depended on D 1 receptor and PKA activation. Although cross-talk with other signaling pathways needs to be studied further, we conclude that DA promotes the differentiation of striatal neurons via stimulation of D 1 receptors and the cAMP/PKA signal transduction pathway.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
A complex chain of intracellular signaling events, critically important in motor control, is activated by the stimulation of D1-like dopamine (DA) receptors in striatal neurons. At corticostriatal synapses on medium spiny neurons, we provide evidence that the D1-like receptor-dependent activation of DA and cyclic adenosine 3',5' monophosphate-regulated phosphoprotein 32 kDa is a crucial step for the induction of both long-term depression (LTD) and long-term potentiation (LTP), two opposing forms of synaptic plasticity. In addition, formation of LTD and LTP requires the activation of protein kinase G and protein kinase A, respectively, in striatal projection neurons. These kinases appear to be stimulated by the activation of D1-like receptors in distinct neuronal populations.
Dopamine and synaptic plasticity in the neostriatum
Journal of Anatomy, 2000
After the unilateral destruction of the dopamine input to the neostriatum there are enduring changes in rat behaviour. These have been ascribed to the loss of dopamine and the animals are often referred to as ' hemiparkinsonian '. In the denervated neostriatum, we have shown that not only are the tyrosine hydroxylase positive boutons missing, but also the medium sized densely spiny output cells have fewer spines. Spines usually have asymmetric synapses on their heads. In a recent stereological study we were able to show that there is a loss of approximately 20 % of asymmetric synapses in the lesioned neostriatum by 1 mo after the lesion. Current experiments are trying to establish the specificity of this loss. So far we have evidence suggesting that there is no obvious preferential loss of synapses from either D1 or D2 receptor immunostained dendrites in the neostriatum with damaged dopamine innervation. These experiments suggest that dopamine is somehow necessary for the maintenance of corticostriatal synapses in the neostriatum. In a different series of experiments slices of cortex and neostriatum were maintained in vitro in such a way as to preserve at least some of the corticostriatal connections. In this preparation we have been able to show that cortical stimulation results in robust excitatory postsynaptic potentials (EPSPs) recorded from inside striatal neurons. Using stimulation protocols derived from the experiments on hippocampal synaptic plasticity we have shown that the usual consequence of trains of high frequency stimulation of the cortex is the depression of the size of EPSPs in the striatal cell. In agreement with similar experiments by others, the effect seems to be influenced by NMDA receptors since the unblocking of these receptors with low Mg ++ concentrations in the perfusate uncovers a potentiation of the EPSPs after trains of stimulation. Dopamine applied in the perfusion fluid round the slices has no effect but pulsatile application of dopamine, close to the striatal cell being recorded from, and in temporal association with the cortical trains, leads to a similar LTP like effect. The reduction of K + channel conductance in the bath with TEA also has the effect of making cortical trains induce potentiation of corticostriatal transmission. TEA applied only to the cell being recorded from has no similar effect ; the cortical stimulation again depresses the EPSP amplitude, so the site of action of TEA may well be presynaptic to the striatal cell. The morphological and physiological experiments may not necessarily be related but it is tempting to suggest that dopamine protects some corticostriatal synapses by potentiating them but that in the absence of dopamine others simply disconnect and are no longer detectable on electron microscopy.