Overexpression of a truncated Kv1.1 channel transgene in the heart (Kv1DN) resulted in mice with a prolonged action potential duration due to marked attenuation of a rapidly activating, slowly inactivating potassium current (I(K,slow1)) in ventricular myocytes. Optical mapping and programmed electrical stimulation revealed inducible ventricular tachycardia due to spatial dispersion of repolarization and refractoriness. Here we show that a delayed rectifier with slower inactivation kinetics (I(K,slow2)) was selectively upregulated in Kv1DN cardiocytes. This electrical remodeling was spatially restricted to myocytes derived from the apex of the left ventricle. Biophysical and pharmacological studies of I(K,slow2) indicate that it resembles Kv2-encoded currents. Northern blot analyses and real-time PCR revealed upregulation of Kv2.1 transcript in Kv1DN mice. Crossbreeding of Kv1DN mice with mice expressing a truncated Kv2.1 polypeptide (Kv2DN) eliminated I(K,slow2). In summary, our data indicate that the spatially restrictive upregulation of Kv2.1-encoded currents underlies the increased dispersion of the repolarization observed in Kv1DN mice.

The functional role of releasable Zn 2؉ in the central nervous system remains unknown. Here we show that zinc transporter 3 (ZnT-3), which maintains a high concentration of Zn 2؉ 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 Zn 2؉ 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 Zn 2؉ 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 Zn 2؉ , may serve an essential control function in assuring spatial specificity of long-lasting synaptic modifications in the neural circuit of a learned behavior.amygdala ͉ synapse ͉ synaptic plasticity ͉ glutamate ͉ GABA L ong-term potentiation (LTP) in afferent inputs to the amygdala is recruited during fear conditioning and used for retention of fear memory (1-5). A subset of glutamatergic neurons in fear conditioning pathways, including pyramidal neurons in the lateral nucleus of the amygdala (LA) where conditioned stimuli (CS) and unconditioned stimuli converge during fear learning (6-9), is enriched in zinc (Zn 2ϩ ) (4). Zn 2ϩ is found to be in a high concentration in synaptic vesicles at various synapses and to be colocalized with the neurotransmitters glutamate or GABA (10,11). Previous studies have demonstrated that this vesicular Zn 2ϩ can be released in a Ca 2ϩ -dependent manner in different regions of the brain, including the hippocampus, cortex, and amygdala, in response to synaptic stimulation at both glutamatergic and GABAergic synapses (11)(12)(13)(14)(15)(16)(17)(18)(19). This set of findings suggested to us the possibility that vesicular zinc may have a role in synaptic plasticity in the neural circuitry of fear learning.Zn 2ϩ has been implicated in a variety of neuronal functions in the mammalian brain both as a paracrine and as an autocrine mediator (20). However, despite intensive efforts the functional role of releasable zinc in synaptic transmission and plasticity remained elusive (10, 20). Here we report that chelatable zinc, released during synaptic activation, is critically involved in control of LTP in the cortico-amygdala pathway, which conveys auditory information about the CS to the amygdala during fear conditioning. We find that zinc acts by suppressing feed-forward inhibition of projection neurons by local circuit interneurons. The pathway-specific expression of zinc-containing cells suggests that this regulatory mechanism may define the spat...