Homeostatic regulation of axonal Kv1.1 channels accounts for both synaptic and intrinsic modifications in the hippocampal 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 to 3 d induces an up-regulation of both synaptic transmission at CA3–CA3 connections and intrinsic excitability of CA3 pyramidal neurons. Intrinsic plasticity was found to be mediated by a reduction of Kv1.1 channel density at the axon initial segment. In activity-deprived circuits, CA3–CA3 synapses were found to express a high release probability, an insensitivity to dendrotoxin, and a lack of depolarization-induced presynaptic facilitation, indicating a reduction in presynaptic Kv1.1 function. Further support for the down-regulation of axonal Kv1.1 channels in activity-deprived neurons was the broadening of action potentials measured in the axon. We conclude that regulation of the axonal Kv1.1 channel constitutes a major mechanism linking intrinsic excitability and synaptic strength that accounts for the functional synergy existing between homeostatic regulation of intrinsic excitability and synaptic transmission.

An Epitope-Specific LGI1-Autoantibody Enhances Neuronal Excitability by Modulating Kv1.1 Channel

“…This mechanism is further supported by the genetic deletion of LGI1, which decreases both Kv1.1 channel density and D-type currents by more than 50% [ 16 ]. As Kv1.1 channels are expressed at both the AIS and presynaptic terminals of CA3 pyramidal neurons [ 17 ], the putative consequence of the decrease in Kv1.1-mediated current is an elevated neuronal excitability and an elevated glutamate release, which both concur to promote synchronous epileptiform discharges. Our results were obtained in vitro, as most results describing the effects of LGI1 manipulation on neuronal excitability.…”

Rescue of normal excitability in LGI1-deficient epileptic neurons

“…Kv1 channels are not only located at the AIS where they determine intrinsic excitability but they are also located at presynaptic terminals where they sharpen the spike and reduce transmitter release (Kole et al, 2007; Boudkkazi et al, 2011; Zbili et al, 2021). Interestingly, the up-regulation of intrinsic neuronal activity in KO-Lgi1 CA3 pyramidal cells comes with a loss of Kv1 channel function at the presynaptic terminal (Seagar et al, 2017).…”

“…Taken together, our data demonstrate that LGI1 determines intrinsic excitability by controlling the expression of Kv1.1 channels at the AIS. Kv1 channels are not only located at the AIS where they determine intrinsic excitability but they are also located at presynaptic terminals where they sharpen the spike and reduce transmitter release (Kole et al, 2007;Boudkkazi et al, 2011;Zbili et al, 2021).…”

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

“…This makes one wonder why LAR would require homeostatic control in the first place. Kv1.1 is implicated with rapid, <10 min, homeostatic regulation of hippocampal excitability 27,28 . Recently, it has been shown that LAR can be flexibly controlled in timeframes <10 min, suppressing the LAR completely by sensitising a threat memory 26 .…”

“…Kv1.1 has been recently shown to be involved in the homeostatic control of firing 27,28 through modulation of the axon initial segment (AIS) 29 . Thus, our behavioural and physiological results isolate a key molecular player in Setd5, Kv1.1, that causes the physiological hypoexcitability phenotype, probably arising through homeostatic misregulation, either by localisation 27 , posttranslational modifications 30 or interactions with auxiliary subunits 31 . current injection.…”