Faculty Opinions recommendation of Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection.

Abstract Layer I neurons in the prefrontal cortex (PFC) exhibit extensive synaptic connections with deep layer neurons, implying their important role in the neural circuit. Study demonstrates that activation of nicotinic acetylcholine receptors (nAChRs) increases excitatory neurotransmission in this layer. Here we found that nicotine selectively increased the amplitude of AMPA receptor (AMPAR)-mediated current and AMPA/NMDA ratio, while without effect on NMDA receptor-mediated current. The augmentation of AMPAR current by nicotine was inhibited by a selective α7-nAChR antagonist methyllycaconitine (MLA) and intracellular calcium chelator BAPTA. In addition, nicotinic effect on mEPSC or paired-pulse ratio was also prevented by MLA. Moreover, an enhanced inward rectification of AMPAR current by nicotine suggested a functional role of calcium permeable and GluA1 containing AMPAR. Consistently, nicotine enhancement of AMPAR current was inhibited by a selective calcium-permeable AMPAR inhibitor IEM-1460. Finally, the intracellular inclusion of synthetic peptide designed to block GluA1 subunit of AMPAR at CAMKII, PKC or PKA phosphorylation site, as well as corresponding kinase inhibitor, blocked nicotinic augmentation of AMPA/NMDA ratio. These results have revealed that nicotine increases AMPAR current by modulating the phosphorylation state of GluA1 which is dependent on α7-nAChR and intracellular calcium.

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Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Nature Communications ◽

10.1038/s41467-019-13809-8 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 17

Author(s):

Farhan Ali ◽

Danielle M. Gerhard ◽

Katherine Sweasy ◽

Santosh Pothula ◽

Christopher Pittenger ◽

...

Keyword(s):

Prefrontal Cortex ◽

Dendritic Spines ◽

Pyramidal Neurons ◽

Gabaergic Neurons ◽

Calcium Transients ◽

Inhibitory Mechanism ◽

Synaptic Inputs ◽

Aspartate Receptor ◽

Antidepressant Effects ◽

Cortical Interneurons

AbstractA subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine’s actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.

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Active control of arousal by a locus coeruleus GABAergic circuit

10.1101/412338 ◽

2018 ◽

Cited By ~ 2

Author(s):

Vincent Breton-Provencher ◽

Mriganka Sur

Keyword(s):

Prefrontal Cortex ◽

Locus Coeruleus ◽

Cognitive Performance ◽

Active Control ◽

Local Population ◽

Gabaergic Neurons ◽

The Other ◽

Lc Circuit ◽

Virus Tracing ◽

The Brain

AbstractArousal and novelty responses linked to locus coeruleus noradrenergic (LC-NA) activity affect cognitive performance. However, the mechanisms that control modes of LC-NA activity remain unknown. Here, we reveal a local population of GABAergic neurons (LC-GABA) capable of modulating LC-NA activity and arousal. Monosynaptic retrograde virus tracing shows that inputs to LC-GABA and LC-NA neurons arise from similar regions, though a few regions provide differential inputs to one subtype over the other. Recordings in the LC demonstrate two modes of LC-GABA responses whereby spiking is either correlated or broadly anti-correlated with LC-NA responses, reflecting anatomically similar and functionally coincident inputs, or differential and non-coincident inputs, to LC-NA and LC-GABA neurons. Coincident inputs control the gain of phasic LC-NA mediated novelty responses, while non-coincident inputs, such as from the prefrontal cortex to LC, alter overall levels of LC-NA responses without affecting response gain. These findings demonstrate distinct modes by which an inhibitory LC circuit regulates the gain and tone of arousal in the brain.

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