Journal of neurophysiology
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Comparative Study
Postsynaptic cell type-dependent cholinergic regulation of GABAergic synaptic transmission in rat insular cortex.
The cerebral cortex consists of multiple neuron subtypes whose electrophysiological properties exhibit diverse modulation patterns in response to neurotransmitters, including noradrenaline and acetylcholine (ACh). We performed multiple whole cell patch-clamp recording from layer V GABAergic interneurons and pyramidal cells of rat insular cortex (IC) to examine whether cholinergic effects on unitary inhibitory postsynaptic currents (uIPSCs) are differentially regulated by ACh receptors, depending on their presynaptic and postsynaptic cell subtypes. In fast-spiking (FS) to pyramidal cell synapses, carbachol (10 μM) invariably decreased uIPSC amplitude by 51.0%, accompanied by increases in paired-pulse ratio (PPR) of the second to first uIPSC amplitude, coefficient of variation (CV) of the first uIPSC amplitude, and failure rate. ⋯ Non-FS to FS/non-FS cell synapses also showed carbachol-induced uIPSC facilitation by 29.2% in about half of the pairs, whereas nearly 40% of pairs showed carbachol-induced suppression of uIPSCs by 40.3%. Carbachol tended to increase uIPSC amplitude in interneuron-to-interneuron synapses with higher PPR, suggesting that carbachol facilitates GABA release in interneuron synapses with lower release probability. These results suggest that carbachol-induced effects on uIPSCs are not homogeneous but preiotropic: i.e., cholinergic modulation of GABAergic synaptic transmission is differentially regulated depending on postsynaptic neuron subtypes.
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Comparative Study
Endogenous inhibition of the trigeminally evoked neurotransmission to cardiac vagal neurons by muscarinic acetylcholine receptors.
Stimulation of the nasal mucosa by airborne irritants or water evokes a pronounced bradycardia accompanied by peripheral vasoconstriction and apnea. The dive response, which includes the trigeminocardiac reflex, is among the most powerful autonomic responses. These responses slow the heart rate and reduce myocardial oxygen consumption. ⋯ Atropine, an mAChR antagonist, facilitated these responses indicating this trigeminally evoked brain stem pathway in vitro is endogenously inhibited by mAChRs. Tropicamide, an m4 mAChR antagonist, prevented the inhibitory action of the muscarinic agonist bethanechol. These results indicate that the glutamatergic synaptic neurotransmission in the trigeminally evoked pathway to CVNs is endogenously inhibited in vitro by m4 mAChRs.
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Comparative Study
Potentiation of short-latency cortical responses by high-frequency repetitive transcranial magnetic stimulation.
It is generally accepted that low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability, but there is only indirect evidence of its effects despite a large number of studies employing different stimulation parameters. Typically the cortical modulations are inferred through indirect measurements, such as recording the change in electromyographic responses. Recently it has become possible to directly evaluate rTMS-induced changes at the cortical level using electronencephalography (EEG). ⋯ Their latency decreased from the first to the last TMS stimuli, while the amplitude values increased. These results provide the first direct, on-line evaluation of the effects of high-frequency TMS on EEG activity. In addition, the results provide a direct demonstration of cortical potentiation induced by rTMS in humans.
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Comparative Study
Severe and progressive neurotransmitter release aberrations in familial hemiplegic migraine type 1 Cacna1a S218L knock-in mice.
Familial hemiplegic migraine type 1 (FHM1) is caused by mutations in the CACNA1A gene, encoding neuronal presynaptic Ca(V)2.1 (P/Q-type) Ca(2+) channels. These channels mediate neurotransmitter release at many central synapses and at the neuromuscular junction (NMJ). Mutation S218L causes a severe neurological phenotype of FHM and, additionally, ataxia and susceptibility to seizures, delayed brain edema, and fatal coma after minor head trauma. ⋯ The synaptopathy clearly progressed with age, including development of an increased acetylcholine release at low-rate nerve stimulation at physiological extracellular Ca(2+) concentration and further endplate potential broadening. Our results suggest enhanced Ca(2+) influx into motor nerve terminals through S218L-mutated presynaptic Ca(V)2.1 channels, likely because of the earlier reported negative shift of activation potential and reduced inactivation. Similar severe aberrations at central synapses of S218L mutant mice and humans may underlie or contribute to the drastic neurological phenotype.
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Clinical Trial
Deep brain stimulation alleviates parkinsonian bradykinesia by regularizing pallidal activity.
Deep brain stimulation (DBS) of the basal ganglia can alleviate the motor symptoms of Parkinson's disease although the therapeutic mechanisms are unclear. We hypothesize that DBS relieves symptoms by minimizing pathologically disordered neuronal activity in the basal ganglia. In human participants with parkinsonism and clinically effective deep brain leads, regular (i.e., periodic) high-frequency stimulation was replaced with irregular (i.e., aperiodic) stimulation at the same mean frequency (130 Hz). ⋯ Thus we show that clinically useful DBS alleviates motor symptoms by regularizing basal ganglia activity and thereby improving thalamic relay fidelity. This work demonstrates that high-frequency stimulation alone is insufficient to alleviate motor symptoms: DBS must be highly regular. Descriptive models of pathophysiology that ignore the fine temporal resolution of neuronal spiking in favor of average neural activity cannot explain the mechanisms of DBS-induced symptom alleviation.