Abstract
The ability of nitric oxide and acetylcholine to modulate the short-term plasticity of corticostriatal inputs was investigated using current-clamp recordings in BAC mouse brain slices. Glutamatergic responses were evoked by stimulation of corpus callosum in D1 and D2 dopamine receptor-expressing medium spiny neurons (D1-MSNs and D2-MSN, respectively). Paired-pulse stimulation (50 ms intervals) evoked depressing or facilitating responses in subgroups of both D1-MSNs and D2 MSNs. In both neuronal types, glutamatergic responses of cells that displayed paired-pulse depression were not significantly affected by the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP; 100 μM). Conversely, in D1-MSNs and D2-MSNs that displayed paired-pulse facilitation, SNAP did not affect the first evoked response, but significantly reduced the amplitude of the second evoked EPSP, converting paired-pulse facilitation into paired-pulse depression. SNAP also strongly excited cholinergic interneurons and increased their cortical glutamatergic responses acting through a presynaptic mechanism. The effects of SNAP on glutamatergic response of D1-MSNs and D2-MSN were mediated by acetylcholine. The broad-spectrum muscarinic receptor antagonist atropine (25 μM) did not affect paired-pulse ratios and did not prevent the effects of SNAP. Conversely, the broad-spectrum nicotinic receptor antagonist tubocurarine (10 μM) fully mimicked and occluded the effects of SNAP. We concluded that phasic acetylcholine release mediates feedforward facilitation in MSNs through activation of nicotinic receptors on glutamatergic terminals and that nitric oxide, while increasing cholinergic interneurons’ firing, functionally impairs their ability to modulate glutamatergic inputs of MSNs. These results show that nitrergic and cholinergic transmission control the short-term plasticity of glutamatergic inputs in the striatum and reveal a novel cellular mechanism underlying paired-pulse facilitation in this area.
Highlights
The striatum is crucially involved in motor control, action selection and reward-mediated learning (Graybiel, 2005)
The main finding of this study is that paired-pulse facilitation of glutamatergic responses, which is observed in both D1-medium sized spiny neurons (MSNs) and D2-MSNs upon stimulation of the corpus callosum (CC), requires activation of nicotinic receptors and is converted into paired-pulse depression by nitric oxide
We propose that paired-pulse facilitating responses in MSNs resulted from a microcircuit in which cholinergic interneurons produce a form of feed-forward facilitation (Figure 5)
Summary
The striatum is crucially involved in motor control, action selection and reward-mediated learning (Graybiel, 2005). Cholinergic interneurons exert a complex influence in the striatal microcircuits, through activation of nicotinic and muscarinic receptors located both pre- and postsynaptically on several neuronal targets (Pakhotin and Bracci, 2007; Ding et al, 2010) Another striatal interneuronal type, characterized by the ability to generate low-threshold calcium spikes, is the only source of nitric oxide in the striatum and is involved in information processing (Kawaguchi, 1993; Tepper and Bolam, 2004). Lowthreshold calcium spike interneurons (LTSIs) are GABAergic and mediate feed-forward inhibition (Tepper and Bolam, 2004) They could affect the striatal network through activation of nitric oxide Signaling cascades. This technique has the advantage of avoiding the well-known signal distortions arising from poor space-clamp of distal dendritic synaptic inputs (Spruston et al, 1993; Williams and Mitchell, 2008) and of preserving the dynamic interplay between synaptic inputs and dendritic voltage-dependent conductances, which may affect the transmembrane signal eventually reaching the perisomatic spike-generating region of the neuron
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