Intracellular Zn2+ Signaling Facilitates Mossy Fiber Input-Induced Heterosynaptic Potentiation of Direct Cortical Inputs in Hippocampal CA3 Pyramidal Cells

• Published in: The Journal of neuroscience Vol. 39; no. 20; pp. 3812 - 3831
• Main Authors: Eom, Kisang, Hyun, Jung Ho, Lee, Dong-gu, Kim, Sooyun, Jeong, Hyeon-Ju, Kang, Jong-Sun, Ho, Won-Kyung, Lee, Suk-Ho
• Format: Journal Article
• Language: English
• Published: Baltimore Society for Neuroscience 15.05.2019
• Subjects: Calcium; Calcium (extracellular); Calcium (intracellular); Calcium ions; Chelation; Clonal deletion; Cortex; Dendrites; Dendritic structure; Excitability; Hippocampus; Intracellular signalling; Kinases; Long-term potentiation; Potassium channels (voltage-gated); Protein-tyrosine kinase; Protein-tyrosine-phosphatase; Proteins; Pyramidal cells; Rodents; Stimulation; Tyrosine; Zinc; Zinc transporter
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2130-18.2019

Repetitive action potentials (APs) in hippocampal CA3 pyramidal cells (CA3-PCs) backpropagate to distal apical dendrites, and induce calcium and protein tyrosine kinase (PTK)-dependent downregulation of Kv1.2, resulting in long-term potentiation of direct cortical inputs and intrinsic excitability (LTP-IE). When APs were elicited by direct somatic stimulation of CA3-PCs from rodents of either sex, only a narrow window of distal dendritic [Ca2+] allowed LTP-IE because of Ca2+-dependent coactivation of PTK and protein tyrosine phosphatase (PTP), which renders non-mossy fiber (MF) inputs incompetent in LTP-IE induction. High-frequency MF inputs, however, could induce LTP-IE at high dendritic [Ca2+] of the window. We show that MF input-induced Zn2+ signaling inhibits postsynaptic PTP, and thus enables MF inputs to induce LTP-IE at a wide range of [Ca2+]i values. Extracellular chelation of Zn2+ or genetic deletion of vesicular zinc transporter abrogated the privilege of MF inputs for LTP-IE induction. Moreover, the incompetence of somatic stimulation was rescued by the inhibition of PTP or a supplement of extracellular zinc, indicating that MF input-induced increase in dendritic [Zn2+] facilitates the induction of LTP-IE by inhibiting PTP. Consistently, high-frequency MF stimulation induced immediate and delayed elevations of [Zn2+] at proximal and distal dendrites, respectively. These results indicate that MF inputs are uniquely linked to the regulation of direct cortical inputs owing to synaptic Zn2+ signaling.