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Cholinergic modulation of local pyramid-interneuron synapses exhibiting divergent short-term dynamics in rat sensory cortex.

ABSTRACT: Acetylcholine (ACh) influences attention, short-term memory, and sleep/waking transitions, through its modulatory influence on cortical neurons. It has been proposed that behavioral state changes mediated by ACh result from its selective effects on the intrinsic membrane properties of diverse cortical inhibitory interneuron classes. ACh has been widely shown to reduce the strength of excitatory (glutamatergic) synapses. But past studies using extracellular stimulation have not been able to examine the effects of ACh on local cortical connections important for shaping sensory processing. Here, using dual intracellular recording in slices of rat somatosensory cortex, we show that reduction of local excitatory input to inhibitory neurons by ACh is coupled to differences in the underlying short-term synaptic plasticity (STP). In synapses with short-term depression, where successive evoked excitatory postsynaptic potentials (EPSPs; >5 Hz) usually diminish in strength (short-term depression), cholinergic agonist (5-10 microM carbachol (CCh)) reduced the amplitude of the first EPSP in an evoked train, but CCh's net effect on subsequent EPSPs rapidly diminished. In synapses where successive EPSPs increased in strength (facilitation), the effect of CCh on later EPSPs in an evoked train became progressively greater. The effect of CCh on both depressing and facilitating synapses was blocked by the muscarinic antagonist, 1-5 microM atropine. It is suggested that selective influence on STP contributes fundamentally to cholinergic "switching" between cortical rhythms that underlie different behavioral states.

SUBMITTER: Levy RB

PROVIDER: S-EPMC2483424 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Cholinergic modulation of local pyramid-interneuron synapses exhibiting divergent short-term dynamics in rat sensory cortex.

Levy Robert B RB Reyes Alex D AD Aoki Chiye C

Brain research 20080406

Acetylcholine (ACh) influences attention, short-term memory, and sleep/waking transitions, through its modulatory influence on cortical neurons. It has been proposed that behavioral state changes mediated by ACh result from its selective effects on the intrinsic membrane properties of diverse cortical inhibitory interneuron classes. ACh has been widely shown to reduce the strength of excitatory (glutamatergic) synapses. But past studies using extracellular stimulation have not been able to exami ...[more]

PMID: 18482715

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Project description:Balance between cholinergic and dopaminergic signaling is central to striatal control of movement and cognition. In dystonia, a common disorder of movement, anticholinergic therapy is often beneficial. This observation suggests there is a pathological increase in cholinergic tone, yet direct confirmation is lacking. In DYT1, an early-onset genetic form of dystonia caused by a mutation in the protein torsinA (TorA), the suspected heightened cholinergic tone is commonly attributed to faulty dopamine D2 receptor (D2R) signaling where D2R agonists cause excitation of striatal cholinergic interneurons (ChIs), rather than the normal inhibition of firing observed in wild-type animals, an effect known as "paradoxical excitation". Here, we provide for the first time direct measurement of elevated striatal extracellular acetylcholine (ACh) in a knock-in mouse model of human DYT1 dystonia (TorA?E/+ mice), confirming a striatal hypercholinergic state. We hypothesized that this elevated extracellular ACh might cause chronic over-activation of muscarinic acetylcholine receptors (mAChRs) and disrupt normal D2R function due to their shared coupling to Gi/o-proteins. We tested this concept in vitro first using a broad-spectrum mAChR antagonist, and then using a M2/M4 mAChR selective antagonist to specifically target mAChRs expressed by ChIs. Remarkably, we found that mAChR inhibition reverses the D2R-mediated paradoxical excitation of ChIs recorded in slices from TorA?E/+ mice to a typical inhibitory response. Furthermore, we recapitulated the paradoxical D2R excitation of ChIs in striatal slices from wild-type mice within minutes by simply increasing cholinergic tone through pharmacological inhibition of acetylcholinesterase (AChE) or by prolonged agonist activation of mAChRs. Collectively, these results show that enhanced mAChR tone itself is sufficient to rapidly reverse the polarity of D2R regulation of ChI excitability, correcting the previous notion that the D2R mediated paradoxical ChI excitation causes the hypercholinergic state in dystonia. Further, using a combination of genetic and pharmacological approaches, we found evidence that this switch in D2R polarity results from a change in coupling from the preferred Gi/o pathway to non-canonical ?-arrestin signaling. These results highlight the need to fully understand how the mutation in TorA leads to pathologically heightened extracellular ACh. Furthermore the discovery of this novel ACh-dopamine interaction and the participation of ?-arrestin in regulation of cholinergic interneurons is likely important for other basal ganglia disorders characterized by perturbation of ACh-dopamine balance, including Parkinson and Huntington diseases, l-DOPA-induced dyskinesia and schizophrenia.

Dataset Information

Cholinergic modulation of local pyramid-interneuron synapses exhibiting divergent short-term dynamics in rat sensory cortex.

Publications

Cholinergic modulation of local pyramid-interneuron synapses exhibiting divergent short-term dynamics in rat sensory cortex.

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