Active propagation of dendritic electrical signals in C. elegans.

Active propagation of electrical signals in C. elegans neurons requires ion channels capable of regenerating membrane potentials. Here we report regenerative depolarization of a major gustatory sensory neuron, ASEL. Whole-cell patch-clamp recordings in vivo showed supralinear depolarization of ASEL upon current injection. Furthermore, stimulation of animal's nose with NaCl evoked all-or-none membrane depolarization in ASEL. Mutant analysis showed that EGL-19, the α1 subunit of L-type voltage-gated Ca2+ channels, is essential for regenerative depolarization of ASEL. ASEL-specific knock-down of EGL-19 by RNAi demonstrated that EGL-19 functions in C. elegans chemotaxis along an NaCl gradient. These results demonstrate that a natural substance induces regenerative all-or-none electrical signals in dendrites, and that these signals are essential for activation of sensory neurons for chemotaxis. As in other vertebrate and invertebrate nervous systems, active information processing in dendrites occurs in C. elegans, and is necessary for adaptive behavior.

A silent eligibility trace enables dopamine-dependent synaptic plasticity for reinforcement learning in the mouse striatum.

Dopamine-dependent synaptic plasticity is a candidate mechanism for reinforcement learning. A silent eligibility trace - initiated by synaptic activity and transformed into synaptic strengthening by later action of dopamine - has been hypothesized to explain the retroactive effect of dopamine in reinforcing past behaviour. We tested this hypothesis by measuring time-dependent modulation of synaptic plasticity by dopamine in adult mouse striatum, using whole-cell recordings. Presynaptic activity followed by postsynaptic action potentials (pre-post) caused spike-timing-dependent long-term depression in D1-expressing neurons, but not in D2 neurons, and not if postsynaptic activity followed presynaptic activity. Subsequent experiments focused on D1 neurons. Applying a dopamine D1 receptor agonist during induction of pre-post plasticity caused long-term potentiation. This long-term potentiation was hidden by long-term depression occurring concurrently and was unmasked when long-term depression blocked an L-type calcium channel antagonist. Long-term potentiation was blocked by a Ca2+ -permeable AMPA receptor antagonist but not by an NMDA antagonist or an L-type calcium channel antagonist. Pre-post stimulation caused transient elevation of rectification - a marker for expression of Ca2+ -permeable AMPA receptors - for 2-4-s after stimulation. To test for an eligibility trace, dopamine was uncaged at specific time points before and after pre- and postsynaptic conjunction of activity. Dopamine caused potentiation selectively at synapses that were active 2-s before dopamine release, but not at earlier or later times. Our results provide direct evidence for a silent eligibility trace in the synapses of striatal neurons. This dopamine-timing-dependent plasticity may play a central role in reinforcement learning.

Behavioral flexibility is increased by optogenetic inhibition of neurons in the nucleus accumbens shell during specific time segments.

Behavioral flexibility is vital for survival in an environment of changing contingencies. The nucleus accumbens may play an important role in behavioral flexibility, representing learned stimulus-reward associations in neural activity during response selection and learning from results. To investigate the role of nucleus accumbens neural activity in behavioral flexibility, we used light-activated halorhodopsin to inhibit nucleus accumbens shell neurons during specific time segments of a bar-pressing task requiring a win-stay/lose-shift strategy. We found that optogenetic inhibition during action selection in the time segment preceding a lever press had no effect on performance. However, inhibition occurring in the time segment during feedback of results--whether rewards or nonrewards--reduced the errors that occurred after a change in contingency. Our results demonstrate critical time segments during which nucleus accumbens shell neurons integrate feedback into subsequent responses. Inhibiting nucleus accumbens shell neurons in these time segments, during reinforced performance or after a change in contingencies, increases lose-shift behavior. We propose that the activity of nucleus shell accumbens shell neurons in these time segments plays a key role in integrating knowledge of results into subsequent behavior, as well as in modulating lose-shift behavior when contingencies change.

A Ca(2+) threshold for induction of spike-timing-dependent depression in the mouse striatum.

The striatum is the principal input nucleus of the basal ganglia, receiving glutamatergic afferents from the cerebral cortex. There is much interest in mechanisms of synaptic plasticity in the corticostriatal synapses. We used two-photon microscopy and whole-cell recording to measure changes in intracellular calcium concentration ([Ca(2+)](i)) associated with spike-time-dependent plasticity in mouse striatum. Uncaging glutamate adjacent to a dendritic spine caused a postsynaptic potential at the soma and a rise in spine [Ca(2+)](i). Action potentials elicited at the soma raised both dendrite and spine [Ca(2+)](i). Pairing protocols in which glutamate uncaging preceded action potentials by 10 ms (pre-post protocol) produced supralinear increases in spine [Ca(2+)](i) compared with the sum of increases seen with uncaging and action potentials alone, or timing protocols in which the uncaging followed the action potentials (post-pre protocols). The supralinear component of the increases in [Ca(2+)](i) were eliminated by the voltage-sensitive calcium channel blocker nimodipine. In the adjacent parent dendrites, the increases in [Ca(2+)](i) were neither supralinear nor sensitive to the relative pre-post timing. In parallel experiments, we investigated the effects of these pairing protocols on spike-timing-dependent synaptic plasticity. Long-term depression (t-LTD) of corticostriatal inputs was induced by pre-post but not post-pre protocols. Intracellular calcium chelators and calcium antagonists blocked pre-post t-LTD, confirming that elevated calcium entering via voltage-sensitive calcium channels is necessary for t-LTD. These findings confirm a spine [Ca(2+)](i) threshold for induction of t-LTD in the corticostriatal pathway, mediated by the supralinear increase in [Ca(2+)](i) associated with pre-post induction protocols.

Actions of adenosine A 2A receptors on synaptic connections of spiny projection neurons in the neostriatal inhibitory network.

There is growing evidence that adenosine plays a crucial role in basal ganglia function, particularly in the modulation of voluntary movement. An adenosine-based treatment for Parkinson's disease shows promise in recent clinical studies. Adenosine A(2A) receptors, the receptors involved in this treatment, are highly expressed in the neostriatum. Previous studies have suggested opposing actions of these receptors on synaptic transmission at striatal and pallidal terminals of the same spiny projection neurons, but the cells of origin of the intrastriatal terminals mediating these actions have not been identified. We used dual whole cell recordings to record simultaneously from pairs of striatal cells; this enabled definitive identification of the presynaptic and postsynaptic cells mediating the effects of A(2A) receptors. We found that A(2A) receptors facilitate GABAergic synaptic transmission by intrastriatal collaterals of the spiny projection neurons, consistent with their previously reported actions on synaptic transmission at pallidal terminals. This neuromodulatory action on lateral inhibition in the striatum may underlie, in part, the therapeutic efficacy of adenosine-based treatments for Parkinson's disease.

Simulation of GABA function in the basal ganglia: computational models of GABAergic mechanisms in basal ganglia function.

This chapter outlines current interpretation of computational aspects of GABAergic circuits of the striatum. Recent hypotheses and controversial matters are reviewed. Quantitative aspects of striatal synaptology relevant to computational models are considered, with estimates of the connectivity of the spiny projection neurons and fast-spiking interneurons. Against this background, insights into the computational properties of inhibitory circuits based on analysis and simulation of simple models are discussed. The paper concludes with suggestions for further theoretical and experimental studies.

Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists.

The selective localization of adenosine A2A receptors to the striatopallidal system suggested a new therapeutic approach to the management of Parkinson's disease (PD). The results of behavioral studies using A2A receptor-specific agents in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys highlight the therapeutic potential of A2A antagonists as a novel treatment for PD. However, little is known about the role of A2A receptors in basal ganglia function or their pathophysiologic role in PD. Recently, the authors found that presynaptic A2A receptors modulate GABAergic synaptic transmission in the striatum and globus pallidus (GP), suggesting an A2A receptor-mediated dual modulation of the striatopallidal system. Striatal A2A receptors may increase the excitability of medium spiny neurons (MSNs) by modulating an intrastriatal GABAergic network. In addition, pallidal modulation occurs at striatopallidal MSN terminals located at the GP, enhancing GABA release onto GP projection neurons and directly suppressing their activity. Blockade of these modulatory functions by A2A antagonists could counteract excessive striatopallidal neuronal activity provoked by striatal dopamine depletion in patients with PD, leading to a reversal of parkinsonian motor deficits.

Adenosine modulates the striatal GABAergic inputs to the globus pallidus via adenosine A2A receptors in rats.

Previous studies have shown presynaptic modulation of adenosine A(2A) receptors for GABAergic synaptic transmission in the globus pallidus (GP). The pallidal A(2A) receptor-mediated modulation is caused by an action on the terminals of striatopallidal medium spiny neurons (MSNs) and/or axon collaterals of GP neurons. Herein, we examined the precise target neurons of the A(2A) receptor-mediated modulation. Activation of A(2A) receptors enhanced striatopallidal GABAergic transmission onto GP neurons, accompanied by a reduction in the paired-pulse facilitation, indicating the presynaptic contribution of A(2A) receptors at terminals of striatopallidal MSNs in the GP. Besides, no A(2A) receptor mRNA was detected in GP neurons by single-cell reverse transcription-polymerase chain reaction analysis, implying no contribution of axon collaterals of GP neurons to the A(2A) receptor regulation. These results demonstrate that the target neurons of adenosinergic modulation via A(2A) receptors in the GP are the striatopallidal MSNs.

Presynaptic adenosine A2A receptors enhance GABAergic synaptic transmission via a cyclic AMP dependent mechanism in the rat globus pallidus.

1. We previously reported a presynaptic facilitatory action of A(2A) receptors on GABAergic synaptic transmission in the rat globus pallidus (GP). In the present study we identify the intracellular signalling mechanisms responsible for this facilitatory action of A(2A) receptors, using biochemical and patch-clamp methods in rat GP slices. 2. The adenosine A(2A) receptor selective agonist CGS21680 (1, 10 microM) and the adenylyl cyclase activator forskolin (1, 10 microM) both significantly increased cyclic AMP accumulation in GP slices. The CGS21680 (1 microM)-mediated increase in cyclic AMP was inhibited by the A(2A) receptor selective antagonist KF17837 (10 microM). 3. In an analysis of miniature inhibitory postsynaptic currents (mIPSCs), forskolin (10 microM) increased the mIPSC frequency without affecting their amplitude distribution, a result similar to that previously reported with CGS21680. 4. The adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22,536, 300 microM) abolished the CGS21680-induced enhancement in the frequency of mIPSCs. 5. H-89 (10 microM), a selective inhibitor for cyclic AMP-dependent protein kinase (PKA), blocked the CGS21680-induced enhancement of the mIPSC frequency. 6. The calcium channel blocker CdCl(2) (100 microM) did not prevent CGS21680 from increasing the frequency of mIPSCs. 7. These results indicate that A(2A) receptor-mediated potentiation of mIPSCs in the GP involves the sequential activation of the A(2A) receptor, adenylyl cyclase, and then PKA, and that this facilitatory modulation could occur independently of presynaptic Ca(2+) influx.