Activation of InsP 3 receptors is sufficient for inducing graded intrinsic 1 plasticity in rat hippocampal pyramidal neurons

27 The synaptic plasticity literature has focused on establishing necessity and sufficiency as 28 two essential and distinct features in causally relating a signaling molecule to plasticity 29 induction, an approach that has been surprisingly lacking in the intrinsic plasticity 30 literature. Here, we complemented the recently established necessity of inositol 31 trisphosphate (InsP 3) receptors (InsP 3 R) in a form of intrinsic plasticity by asking if 32 InsP 3 R activation was sufficient to induce intrinsic plasticity in hippocampal neurons. 33 Specifically, incorporation of D-myo-InsP 3 in the recording pipette reduced input 34 resistance, maximal impedance amplitude and temporal summation, but increased 35 resonance frequency, resonance strength, sag ratio, and impedance phase lead. Strikingly, 36 the magnitude of plasticity in all these measurements was dependent upon [InsP 3 ], 37 emphasizing the graded dependence of such plasticity on InsP 3 R activation. 38 Mechanistically, we found that this InsP 3-induced plasticity depended on 39 hyperpolarization-activated cyclic-nucleotide gated channels. Moreover, this calcium-40 dependent form of plasticity was critically reliant on the release of calcium through 41 InsP 3 Rs, the influx of calcium through N-methyl-D-aspartate receptors and voltage-gated 42 calcium channels, and on the protein kinase A pathway. Our results delineate a causal 43 role for InsP 3 Rs in graded adaptation of neuronal response dynamics, revealing novel 44 regulatory roles for the endoplasmic reticulum in neural coding and homeostasis. 45 3 INTRODUCTION 46