Homeostatic regulation of axonal K_v1.1 channels accounts for both synaptic and intrinsic modifications in CA3 circuit

Abstract

Homeostatic plasticity of intrinsic excitability goes hand-in-hand with homeostatic plasticity of synaptic transmission. However, the mechanisms linking the two forms of homeostatic regulation have not been identified so far. Using electrophysiological, imaging and immunohistochemical techniques, we show here that blockade of excitatory synaptic receptors for 2-3 days induces an up-regulation of synaptic strength at CA3-CA3 connexions and intrinsic excitability of CA3 pyramidal neurons. Activity-deprived connexions were found to express a high release probability, an insensitivity to dendrotoxin, and a lack of depolarization-induced presynaptic facilitation, indicating a loss of presynaptic Kv1.1 function. The down-regulation of Kv1.1 channels in activity-deprived neurons was confirmed by their broader action potentials measured in the axon that were insensitive to dendrotoxin. We conclude that regulation of axonal Kv1.1 channel constitutes a unique mechanism linking intrinsic excitability and synaptic strength that accounts for the functional synergy existing between homeostatic regulation of intrinsic excitability and synaptic transmission.

Recurrent impairments in visual perception and place avoidance across autism models are causally linked in the haploinsufficiency model of intellectual disabilitySetd5

“…5k, Fig. S7), the causes of the physiological hypoexcitability phenotype probably arise through homeostatic misregulation, either by localisation [33], post-translational modifications [45], or interactions with auxiliary subunits [46]. The link between potassium channels and autism is well established [47].…”

“…S7g,h). Given that Kv1.1 has been recently shown to be involved in the homeostatic control of firing [33,34] through modulation of the axon initial segment (AIS) [35], these results indicate that the deficits might not arise due to direct changes in expression but due to homeostatic misregulation. Next, we tested if the dPAG neurons of Ptchd1 Y/and Cul3 +/animals showed similar physiological properties to Setd5 +/neurons.…”

“…Next, we investigated the underlying mechanisms of the hypoexcitable phenotype of the Setd5 +/-dPAG cells. The changes in excitability and spike kinetics are indicative of differences in channel composition that are part of adaptive homeostatic mechanisms [33], suggesting the influence of voltage-gated potassium channels (Kv). Previously published work [23], which studied the transcriptomic changes brought about by a mutation in Setd5 +/-, highlighted significant upregulation in the expression of Kv1.1 channels during development.…”