Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum

Abstract

The dorsal striatum is a large forebrain region involved in action initiation, timing, control, learning and memory. Learning and remembering skilled movement sequences requires the dorsal striatum, and striatal subregions participate in both goal-directed (action-outcome) and habitual (stimulus-response) learning. Modulation of synaptic transmission plays a large part in controlling input to as well as the output from striatal medium spiny projection neurons (MSNs). Synapses in this brain region are subject to short-term modulation, including allosteric alterations in ion channel function and prominent presynaptic inhibition. Two forms of long-term synaptic plasticity have also been observed in striatum, long-term potentiation (LTP) and long-term depression (LTD). LTP at glutamatergic synapses onto MSNs involves activation of NMDA-type glutamate receptors and D1 dopamine or A2A adenosine receptors. Expression of LTP appears to involve postsynaptic mechanisms. LTD at glutamatergic synapses involves retrograde endocannabinoid signaling stimulated by activation of metabotropic glutamate receptors (mGluRs) and D2 dopamine receptors. While postsynaptic mechanisms participate in LTD induction, maintained expression involves presynaptic mechanisms. A similar form of LTD has also been observed at GABAergic synapses onto MSNs. Studies have just begun to examine the roles of synaptic plasticity in striatal-based learning. Findings to date indicate that molecules implicated in induction of plasticity participate in these forms of learning. Neurotransmitter receptors involved in LTP induction are necessary for proper skill and goal-directed instrumental learning. Interestingly, receptors involved in LTP and LTD at glutamatergic synapses onto MSNs of the "indirect pathway" appear to have important roles in habit learning. More work is needed to reveal if and when synaptic plasticity occurs during learning and if so what molecules and cellular processes, both short- and long-term, contribute to this plasticity.

Figure 1

Neurotransmitter and receptor roles in striatal LTP and LTD. A) Diagram showing types of long-term synaptic plasticity at glutamatergic striatal synapses, and the general paradigm for inducing plasticity and examining effects of pharmacological treatments. The white bar indicates time periods during which pharmacological agents can be given to modify induction or expression of LTP or LTD. B) Schematic diagram of mechanisms thought to be involved in striatal LTP. Induction of LTP involves activation of NMDARs, along with either D1 or A2A receptor activation in direct and indirect pathway neurons, respectively. Increases in intracellular calcium trigger biochemical changes, possibly including activation of the calmodulin-dependent protein kinase type II (CAMKIIa). The GPCRs stimulate adenylyl cyclase activity and phosphorylation of DARPP-32 (not shown), but the mechanisms of linking these signaling pathways to LTP expression are not yet known. Expression of LTP is thought to involve AMPAR insertion at the synapse. C) Schematic diagram of mechanisms involved in striatal LTD. Postsynaptic depolarization activates Cav1.3-type voltage-gated calcium channels, while glutamate activates group I mGluRs. The calcium and metabotropic signals converege to stimulate endocannabinoid (EC) synthesis and release. The EC acts on presynaptic CB1 receptors. Combined CB1 activation and presynaptic activity produces a long-lasting decrease in presynaptic release probability (possibly through decreased calcium channel function or more direct effects on vesicle fusion). Arrowheads indicate stimulation, while circular line endings indicate inhibition. D) Listing of neurotransmitter receptor subtypes implicated in LTP and LTD induction. Note that these receptors do not appear to be necessary for maintenance of LTP or LTD once plasticity has been induced.

Figure 2

Striatal-based skill and instrumental/response learning involve different mechanisms and different striatal subregions. Left) Schematic representation of a coronal hemislice of the brain containing the dorstal striatum. Receptors, types of synaptic plasticity and changes in firing of medium spiny neurons (MSNs) associated with skill learning in the dorsomedial striatum (DMS, red) and the dorsolateral striatum (DLS, blue). Involvement of the two subregions in different stages of skill learning are also highlighted. Right) Similar diagram with information about instrumental and response learning. Receptors, types of synaptic plasticity and changes in firing of medium spiny neurons (MSNs) associated with instrumental and response learning in the DMS (red) and the DLS (blue). Involvement of the two subregions in different stages of types of instrumental learning are also highlighted.