Zinc dithizonate staining in the cat hippocampus: Relationship to the mossy-fiber neuropil and postnatal development

Frederickson, Christopher J.; Howell, Gailyn A.; Frederickson, Mary H.

doi:10.1016/0014-4886(81)90214-4

Cited by 62 publications

(14 citation statements)

References 14 publications

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“…Synaptic Zn 2+ accumulation is developmentally regulated, this ion is observed in synaptic vesicles only after the first post-natal week (Frederickson et al, 1981; Nitzan et al, 2002), somewhat resembling developmental KCC2 expression (Lu et al, 1999; Rivera et al, 1999; Lee et al, 2005). While in the mouse hippocampus some vesicular Zn 2+ is observed at postnatal day 6, the levels of this metal are substantially increased during the 2–3 postnatal weeks (Nitzan et al, 2002; Liguz-Lecznar et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of KCC2 Activity by Zinc-Mediated Neurotransmission via the mZnR/GPR39 Receptor

Chorin¹,

Vinograd²,

Fleidervish³

et al. 2011

J. Neurosci.

127

172

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Vesicular Zn2+ regulates postsynaptic neuronal excitability upon its corelease with glutamate. We previously demonstrated that synaptic Zn2+ acts via a distinct metabotropic zinc-sensing receptor (mZnR) in neurons to trigger Ca2+ responses in the hippocampus. Here, we show that physiological activation of mZnR signaling induces enhanced K+/Cl− cotransporter 2 (KCC2) activity and surface expression. As KCC2 is the major Cl− outward transporter in neurons, Zn2+ also triggers a pronounced hyperpolarizing shift in the GABAA reversal potential. Mossy fiber stimulation-dependent upregulation of KCC2 activity is eliminated in slices from Zn2+ transporter 3-deficient animals, which lack synaptic Zn2+. Importantly, activity-dependent ZnR signaling and subsequent enhancement of KCC2 activity are also absent in slices from mice lacking the G-protein-coupled receptor GPR39, identifying this protein as the functional neuronal mZnR. Our work elucidates a fundamentally important role for synaptically released Zn2+ acting as a neurotransmitter signal via activation of a mZnR to increase Cl− transport, thereby enhancing inhibitory tone in postsynaptic cells.

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Section: Discussionmentioning

confidence: 99%

Upregulation of KCC2 Activity by Zinc-Mediated Neurotransmission via the mZnR/GPR39 Receptor

Chorin¹,

Vinograd²,

Fleidervish³

et al. 2011

J. Neurosci.

127

172

View full text Add to dashboard Cite

show abstract

“…Accumulation of synaptic Zn 2+ and increased KCC2 expression are both developmentally regulated (Frederickson et al 1981; Lu et al 1999; Penkowa et al 1999; Rivera et al 1999; Nitzan et al 2002; Payne et al 2003; Stein et al 2004). Zn 2+ release has been difficult to detect in slices from neonatal mice (Frederickson et al 2006) and the absence of KCC2 in these stages yields depolarizing GABA responses (Rivera et al 1999; Lee et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures

Gilad

Shorer

Ketzef

et al. 2015

Neurobiology of Disease

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The aim of this study was to investigate the role of the synaptic metabotropic zinc receptor mZnR/GPR39 in physiological adaptation to epileptic seizures. We previously demonstrated that synaptic activation of mZnR/GPR39 enhances inhibitory drive in the hippocampus by upregulating neuronal K+/Cl− co-transporter 2 (KCC2) activity. Here, we first show that mZnR/GPR39 knockout (KO) adult mice have dramatically enhanced susceptibility to seizures triggered by a single intraperitoneal injection of kainic acid, when compared to wild type (WT) littermates. Kainate also substantially enhances seizure-associated gamma oscillatory activity in juvenile mZnR/GPR39 KO hippocampal slices, a phenomenon that can be reproduced in WT tissue by extracellular Zn2+ chelation. Importantly, kainate-induced synaptic Zn2+ release enhances surface expression and transport activity of KCC2 in WT, but not mZnR/GPR39 KO hippocampal neurons. Kainate-dependent upregulation of KCC2 requires mZnR/GPR39 activation of the Gαq/phospholipase C/extracellular regulated kinase (ERK1/2) signaling cascade. We suggest that mZnR/GPR39-dependent upregulation of KCC2 activity provides homeostatic adaptation to an excitotoxic stimulus by increasing inhibition. As such, mZnR/GPR39 may provide a novel pharmacological target for dampening epileptic seizure activity.

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“…This is because pups (like young kittens (Frederickson et al, 1981) have very few of the neurons (granule neurons) from which the zinc-rich mossy axons arise (Altman and Das, 1965). (One should note, however, that rat pups do have scattered, mature-appearing mossy axons within a week or so of birth.…”

Section: Age Of Subjectmentioning

confidence: 97%

Synaptic release of zinc from brain slices: Factors governing release, imaging, and accurate calculation of concentration

Frederickson

Giblin

Balaji

et al. 2006

Journal of Neuroscience Methods

111

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Zinc dithizonate staining in the cat hippocampus: Relationship to the mossy-fiber neuropil and postnatal development

Cited by 62 publications

References 14 publications

Upregulation of KCC2 Activity by Zinc-Mediated Neurotransmission via the mZnR/GPR39 Receptor

Upregulation of KCC2 Activity by Zinc-Mediated Neurotransmission via the mZnR/GPR39 Receptor

Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures

Synaptic release of zinc from brain slices: Factors governing release, imaging, and accurate calculation of concentration

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