Using c-kit to genetically target cerebellar molecular layer interneurons in adult mice

Amat, Samantha B.; Rowan, Matthew J. M.; Gaffield, Michael A.; Bonnan, Audrey; Taniguchi, Hiroki; Christie, Jason M.

doi:10.1371/journal.pone.0179347

Cited by 30 publications

(39 citation statements)

References 58 publications

(77 reference statements)

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“…As c‐kit is expressed in both PCs and MLIs during development, we could not use the c‐kit‐ Cre line to selectively knockout Grin1 in MLIs (Amat et al . ). Thus, we used Pvalb ‐ Cre transgenic mice to knockout GluN1 in parvalbumin (PV)‐positive MLIs and PCs (MLI/PC‐ Grin1 cKO) (Fig.…”

Section: Resultsmentioning

confidence: 97%

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Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Kono

Kakegawa

Yoshida

et al. 2018

The Journal of Physiology

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Key points NMDA receptors (NMDARs) are required for long‐term depression (LTD) at parallel fibre–Purkinje cell synapses, but their cellular localization and physiological functions in vivo are unclear. NMDARs in molecular‐layer interneurons (MLIs), but not granule cells or Purkinje cells, are required for LTD, but not long‐term potentiation induced by low‐frequency stimulation of parallel fibres. Nitric oxide produced by NMDAR activation in MLIs probably mediates LTD induction. NMDARs in granule cells or Purkinje cells are dispensable for motor learning during adaptation of horizontal optokinetic responses. Abstract Long‐term potentiation (LTP) and depression (LTD), which serve as cellular synaptic plasticity models for learning and memory, are crucially regulated by N‐methyl‐d‐aspartate receptors (NMDARs) in various brain regions. In the cerebellum, LTP and LTD at parallel fibre (PF)–Purkinje cell (PC) synapses are thought to mediate certain forms of motor learning. However, while NMDARs are essential for LTD in vitro, their cellular localization remains controversial. In addition, whether and how NMDARs mediate motor learning in vivo remains unclear. Here, we examined the contribution of NMDARs expressed in granule cells (GCs), PCs and molecular‐layer interneurons (MLIs) to LTD/LTP and motor learning by generating GC‐, PC‐ and MLI/PC‐specific knockouts of Grin1, a gene encoding an obligatory GluN1 subunit of NMDARs. While robust LTD and LTP were induced at PF–PC synapses in GC‐ and PC‐specific Grin1 (GC‐Grin1 and PC‐Grin1, respectively) conditional knockout (cKO) mice, only LTD was impaired in MLI/PC‐specific Grin1 (MLI/PC‐Grin1) cKO mice. Application of diethylamine nitric oxide (NO) sodium, a potent NO donor, to the cerebellar slices restored LTD in MLI/PC‐Grin1 cKO mice, suggesting that NO is probably downstream to NMDARs. Furthermore, the adaptation of horizontal optokinetic responses (hOKR), a cerebellar motor learning task, was normally observed in GC‐Grin1 cKO and PC‐Grin1 cKO mice, but not in MLI/PC‐Grin1 cKO mice. These results indicate that it is the NMDARs expressed in MLIs, but not in PCs or GCs, that play important roles in LTD in vitro and motor learning in vivo.

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Section: Resultsmentioning

confidence: 97%

“…1B and C). As c-kit is expressed in both PCs and MLIs during development, we could not use the c-kit-Cre line to selectively knockout Grin1 in MLIs (Amat et al 2017).…”

Section: Generation Of Cell Type-specific Conditional Grin1 Knockout mentioning

confidence: 99%

Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Kono

Kakegawa

Yoshida

et al. 2018

The Journal of Physiology

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“…Heterozygous adult Kit::Cre mice (Amat et al, 2017) of both genders were used for all experiments (in vivo and ex vivo:>10 and>7 weeks of age, respectively).…”

Section: Methodsmentioning

confidence: 99%

Inhibition gates supralinear Ca2+ signaling in Purkinje cell dendrites during practiced movements

Gaffield

Rowan

Amat

et al. 2018

eLife

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Motor learning involves neural circuit modifications in the cerebellar cortex, likely through re-weighting of parallel fiber inputs onto Purkinje cells (PCs). Climbing fibers instruct these synaptic modifications when they excite PCs in conjunction with parallel fiber activity, a pairing that enhances climbing fiber-evoked Ca2+ signaling in PC dendrites. In vivo, climbing fibers spike continuously, including during movements when parallel fibers are simultaneously conveying sensorimotor information to PCs. Whether parallel fiber activity enhances climbing fiber Ca2+ signaling during motor behaviors is unknown. In mice, we found that inhibitory molecular layer interneurons (MLIs), activated by parallel fibers during practiced movements, suppressed parallel fiber enhancement of climbing fiber Ca2+ signaling in PCs. Similar results were obtained in acute slices for brief parallel fiber stimuli. Interestingly, more prolonged parallel fiber excitation revealed latent supralinear Ca2+ signaling. Therefore, the balance of parallel fiber and MLI input onto PCs regulates concomitant climbing fiber Ca2+ signaling.

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“…Since our results show that nicotine directly activates VIP cells and indirectly depolarizes Pyr cells, it is possible that nicotinic depolarization of Pyr cells depends on activation of VIP interneurons. To address this, we silenced VIP interneurons using inhibitory DREADDs that primarily prevent synaptic release of neurotransmitter from HM4D‐expressing cells (Amat et al, ; Lichtenberg et al, ; Stachniak, Ghosh, & Sternson, ). Cre‐inducible AAV hM4D viruses were injected into the auditory cortex of VIP‐Cre mice (Figure a), and inhibitory DREADDs expressed in VIP neurons were activated by the agonist CNO (100 nM).…”

Section: Resultsmentioning

confidence: 99%

Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex

Askew

López

Wood

et al. 2019

Synapse

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Nicotine activates nicotinic acetylcholine receptors and improves cognitive and sensory function, in part by its actions in cortical regions. Physiological studies show that nicotine amplifies stimulus‐evoked responses in sensory cortex, potentially contributing to enhancement of sensory processing. However, the role of specific cell types and circuits in the nicotinic modulation of sensory cortex remains unclear. Here, we performed whole‐cell recordings from pyramidal (Pyr) neurons and inhibitory interneurons expressing parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) in mouse auditory cortex, in vitro. Bath application of nicotine strongly depolarized and excited VIP neurons, weakly depolarized Pyr neurons, and had no effect on the membrane potential of SOM or PV neurons. The use of receptor antagonists showed that nicotine's effects on VIP and Pyr neurons were direct and indirect, respectively. Nicotine also enhanced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Pyr, VIP, and SOM, but not PV, cells. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we show that chemogenetic inhibition of VIP neurons prevents nicotine's effects on Pyr neurons. Since VIP cells preferentially contact other inhibitory interneurons, we suggest that nicotine drives VIP cell firing to disinhibit Pyr cell somata, potentially making Pyr cells more responsive to auditory stimuli. In parallel, activation of VIP cells also directly inhibits Pyr neurons, likely altering integration of other synaptic inputs. These cellular and synaptic mechanisms likely contribute to nicotine's beneficial effects on cognitive and sensory function.

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Using c-kit to genetically target cerebellar molecular layer interneurons in adult mice

Cited by 30 publications

References 58 publications

Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Interneuronal NMDA receptors regulate long‐term depression and motor learning in the cerebellum

Inhibition gates supralinear Ca2+ signaling in Purkinje cell dendrites during practiced movements

Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex

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