Zn2+ neurotransmission during kainate-induced in-vitro seizure-like activity results in upregulation of KCC2 activity via mZnR/GPR39

Research output: Contribution to journalArticle

Abstract

Background: Synaptic Zn2+ is stored in pre-synaptic vesicles
and is co-released with glutamate in a sub-population of
glutamatergic nerve terminals. A distinct metabotropic Zn2+-
sensing receptor (mZnR), was shown by our lab to trigger
intracellular Ca2+ rise following synaptic Zn2+ release in CA3
hippocampal neurons. We have shown that exogenous Zn2+ or
Zn2+ released by physiologic stimulation of hippocampal
mossy fibers upregulates KCC2 activity via mZnR/GPR39
by increasing its surface expression. KCC2 is the principal
Cl-
-outward transporter in mature neurons and its upregulation
by mZnR/GPR39 signaling is sufficient to produce a hyperpolarizing shift in GABA reversal potential (EGABA) and may
thus alter neuronal excitability.
Results: KCC2 activity was monitored by measuring the
rate of NH4
+ influx into neurons using fluorescent imaging.
Mouse brain slices from mZnR WT animals incubated with
the excitotoxin kainate demonstrated a nearly two-fold increase in KCC2 activity in CA3 hippocampal neurons compared to controls. This upregulation of KCC2 activity was
abolished in slices treated with the cell impermeable Zn2+
chelators CaEDTA and tricine. Furthermore, kainate treatment did not change KCC2 activity in the presence of Gαq,
PLC and MEK1/2 inhibitors that eliminate GPR39/mZnR
signaling. Importantly, in slices from mZnR KO animals
kainate did not significantly change KCC2 activity.
Conclusions: GPR39/mZnR activation by Zn2+ during kainateinduced seizure-like activity results in upregulation of KCC2
activity in CA3 hippocampal neurons. We suggest that synaptic
Zn2+ released during excitatory activity may initially enhance
inhibitory tone, providing an intrinsic homeostatic mechanism.
Original languageEnglish
Pages (from-to)s46
JournalJournal of Molecular Neuroscience
Volume51
Issue numberSuppl.1
DOIs
StatePublished - 2013

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