Review
Dopamine-mediated regulation of corticostriatal synaptic plasticity

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The striatum represents the main input into the basal ganglia. Neurons projecting from the striatum receive a large convergence of afferents from all areas of the cortex and transmit neural information to the basal ganglia output structures. Corticostriatal transmission is essential in the regulation of voluntary movement, in addition to behavioural control, cognitive function and reward mechanisms. Long-term potentiation (LTP) and long-term depression (LTD), the two main forms of synaptic plasticity, are both represented at corticostriatal synapses and strongly depend on the activation of dopamine receptors. Here, we discuss possible feedforward and feedback mechanisms by which striatal interneurons, in association with striatal spiny neurons and endogenous dopamine, influence the formation and maintenance of both LTP and LTD. We also propose a model in which the spontaneous membrane oscillations of neurons projecting from the striatum (named ‘up’ and ‘down’ states), in addition to the pattern of release of endogenous dopamine, bias the synapse towards preferential induction of LTP or LTD. Finally, we discuss how endogenous dopamine crucially influences changes in synaptic plasticity induced by pathological stimuli, such as energy deprivation.

Introduction

The striatum represents the main input into the basal ganglia; neurons projecting from the striatum receive a large convergence of afferents from all areas of the cortex, which has a crucial integrative and computational role, leading to the acquisition of motor and cognitive action sequences 1, 2.

Medium GABA-containing spiny neurons represent the main (>95%) neuronal population of the striatum and modulate the output signals of the basal ganglia through interaction with three major subclasses of interneurons: fast-spiking, parvalbumin-containing, GABA-releasing interneurons; low-threshold spike (LTS), NADPH diaphorase- and somatostatin-positive interneurons; and large cholinergic aspiny interneurons 3, 4. Cortical inputs reach GABA-releasing neurons that output from the striatum, on which they exert a powerful glutamate-mediated excitatory influence. Dopaminergic afferents from the substantia nigra pars compacta (SNpc) converge with these cortical signals, supporting the role of the striatum in the processing of reward signals that depends on the association of dopamine-mediated transmission and sensory cues from cortical areas 2, 5.

Long-lasting, activity-dependent synaptic changes are thought to underlie the ability of the brain to translate experiences into memories and seem to represent the cellular model underlying learning and memory processes.

The two ‘classic’ forms of long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), are widely expressed at excitatory synapses throughout the brain and have both been described at corticostriatal connections, at which they might underlie motor-skill learning, cognitive performance and reward mechanisms 2, 6, 7. Dopamine influences the physiological processes of the striatum through several mechanisms, including the modulation of various voltage-gated currents. The induction of synaptic plasticity in the striatum requires interaction between dopamine and other neurotransmitters, including glutamate primarily [functioning at both ionotropic (NMDA and AMPA) and metabotropic receptors] and also acetylcholine, nitric oxide (NO) and endogenous cannabinoids (ECBs). Dopamine, functioning at dopamine D1-like (D1 and D5) and D2-like (D2, D3 and D4) receptors crucially influences both the induction and the reversal of neuroplasticity at corticostriatal synapses.

The requirement of dopamine for the induction of striatal LTP and LTD makes these two forms of synaptic plasticity unique in comparison with long-term synaptic changes in other brain areas. In fact, although endogenous dopamine is required for the maintenance and modulation of hippocampal plastic changes [8], it does not seem to be implicated in their induction. Conversely, in the striatum, a certain level of endogenous dopamine seems to be required for the induction of both LTP and LTD.

In recent years, significant progress has been made in the field of synaptic plasticity, including elucidation of the role of dopamine in its regulation. Nevertheless, several questions about dopamine-mediated control of corticostriatal neuroplasticity are still unanswered. How does the pattern of dopamine release from the SNpc preferentially induce LTD or LTP? How do the two different classes of dopamine receptors cooperate to induce these forms of neuronal plasticity? How do various pathological conditions associated with acute and neurodegenerative diseases affect dopamine-dependent corticostriatal synaptic plasticity? Finally, do these forms of dopamine-dependent plasticity represent the neuronal correlate of reward processes?

Section snippets

An old question: is dopamine excitatory or inhibitory?

The precise mechanism by which dopamine regulates the physiological activity of striatal target cells is not completely understood. In vivo, pioneering electrophysiological studies have suggested both excitatory [9] and inhibitory actions [10] of dopamine on striatal neurons. The first in vitro studies showed that both D1 and D2 receptors modulate multiple voltage-dependent currents in medium spiny neurons that project from the striatum.

Dopamine, through its interaction with D1 receptors, can

The discovery of long-term depression

Since the beginning of the 1990s, pioneering in vitro studies of long-term activity-dependent modification at glutamatergic corticostriatal synapses have demonstrated that high-frequency stimulation (HFS) of corticostriatal fibres using a train of pulses at 100 Hz, in association with postsynaptic neuron firing, consistently induced LTD of glutamatergic synaptic transmission onto striatal-output neurons 19, 20, 21. This form of synaptic plasticity was not affected by bath application of NMDA

Possible feedforward and feedback mechanisms in long-term depression

A crucial synaptic balance between dopamine and acetylcholine exists in the striatum, and acetylcholine seems to be a key mediator of dopamine-dependent striatal plasticity and learning [25]. Dopamine release is strongly modulated by the activation of nicotinic receptors located on dopaminergic nerve terminals in the striatum [26], and activation of nicotinic receptors, during synaptic activation by HFS, seems to interact with the dopaminergic actions that lead to striatal LTD [27].

Long-term potentiation: a parallel, but opposite, form of synaptic plasticity

Similar to LTD, LTP is considered a cellular-level model of learning and is crucial for the storage and retrieval of neural information in several brain areas [36]. In the striatum, LTP was initially revealed by removing Mg2+ ions from the external medium [37]. By deinactivating NMDA receptor channels, this experimental condition revealed a component of the excitatory postsynaptic potential (EPSP) that was potentiated by repetitive, tetanic activation of corticostriatal fibres and that was

Dopamine-mediated control of pathological forms of neuronal plasticity

Although the accepted hypothesis of synaptic plasticity considers that the enduring changes of glutamatergic transmission are ‘physiological’ synaptic correlates of learning and memory processes, many of the molecular pathways involved in the induction and maintenance of LTP and LTD are also observed during synaptic plastic changes induced by pathological stimuli. Dopamine also seems to crucially influence these ‘pathological’ forms of synaptic plasticity.

Controversies

Characterization of the physiological action of dopamine in the modulation of long-lasting striatal synaptic changes is complicated by the differential distribution of D1 and D2 receptors. In fact, although still controversial, the prevailing opinion is that D1 and D2 receptors are segregated in two subpopulations of projecting GABA-releasing spiny neurons, forming two large efferent streams that are thought to differ in their axonal targets [59] (Figure 1).

According to this hypothesis, D1

Concluding remarks and future perspectives

Activation of dopamine receptors seems to represent a crucial factor in the formation of the two alternative forms of neuroplasticity at corticostriatal synapses. LTP and LTD are strongly influenced by dopamine produced by the substantia nigra and lost after pharmacological manipulation or genetic disruption at different levels of the dopamine-mediated signalling pathway. Interestingly, dopamine is also involved in the control of the induction of LTD exerted by other neurotrasmitters: dopamine,

Acknowledgements

This work has been supported by the Fondo per gli Investimenti della Ricerca di Base 2003 (FIRB2003), Ricerca Scientifica di Rilevante Interesse Nazionale 2005 (PRIN2005), Progetti Finalizzati e Strategici Ministero della Salute 2004, Progetto Dopamina Istituto Superiore della Sanità and Fondazione Cassa di Risparmio Perugia (P.C.).

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