Synaptically released zinc gates long-term potentiation in fear conditioning pathways

doi:10.1073/pnas.0607131103

Synaptically released zinc gates long-term potentiation in fear conditioning pathways

*Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478;
^†Department of Genetics, Rutgers University, Piscataway, NJ 08854; and
^‡Howard Hughes Medical Institute, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032

Contributed by Eric R. Kandel, August 16, 2006

Abstract

The functional role of releasable Zn²⁺ in the central nervous system remains unknown. Here we show that zinc transporter 3 (ZnT-3), which maintains a high concentration of Zn²⁺ in synaptic vesicles and serves as a marker for zinc-containing neurons, is enriched in the lateral nucleus of the amygdala and in the temporal area 3 of the auditory cortex, an area that conveys information about the auditory conditioned stimulus to the lateral nucleus of the amygdala, but not in other conditioned stimulus areas located in the auditory thalamus. Using whole-cell recordings from amygdala slices, we demonstrated that activity-dependent release of chelatable Zn²⁺ is required for the induction of spike timing-dependent long-term potentiation in cortical input to the amygdala implicated in fear learning. Our data indicate that synaptically released Zn²⁺ enables long-term potentiation at the cortico-amygdala synapses by depressing feed-forward GABAergic inhibition of principal neurons. This regulatory mechanism, implicating pathway-dependent release of Zn²⁺, may serve an essential control function in assuring spatial specificity of long-lasting synaptic modifications in the neural circuit of a learned behavior.

Footnotes

^§To whom correspondence may be addressed. E-mail: erk5{at}columbia.edu or vadimb{at}mclean.harvard.edu
Author contributions: V.Y.B. designed research; S.A.K., S.T., and J.J. performed research; E.R.K. and G.P.S. contributed new reagents/analytic tools; S.A.K., S.T., J.J., and G.P.S. analyzed data; and E.R.K., G.P.S., and V.Y.B. wrote the paper.
Conflict of interest statement: E.R.K. is one of four founders of Memory Pharmaceuticals and Chairman of its Scientific Advisory Board. In addition, E.R.K. is a member of the Scientific Advisory Board of Brain Cells.
Abbreviations:

LA,

lateral nucleus of the amygdala;

EPSP,

excitatory postsynaptic potential;

IPSP,

inhibitory postsynaptic potential;

IPSC,

inhibitory postsynaptic current;

sIPSC,

spontaneous IPSC;

CS,

conditioned stimulus;

LTP,

long-term potentiation;

AP,

action potential;

TPEN,

N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine;

PTX,

picrotoxin;

GRP,

gastrin-releasing peptide;

CNQX,

6-cyano-7-nitroquinoxaline-2,3-dione;

EC,

external capsule;

GABAAR,

GABAA receptor.