Liebergall, S. R. | Search bioRxiv

bioRxiv2026

Use-dependent regulation of the axonal action potential in parvalbumin-expressing interneurons

The action potential (AP) is thought to be generated at the axon initial segment and to faithfully propagate along the axon. However, data from both invertebrate and mammalian systems show that the axon is an underappreciated locus of activity modulation and neuronal computation. We assessed axonal AP propagation in neocortical parvalbumin-expressing interneurons (PVINs) during prolonged, high-frequency activity through paired whole-cell somatic and axon-attached patch clamp recordings in acute brain slices from mouse and human. We found that PV-IN axonal AP propagation remains robust during prolonged activity at moderate frequencies, such as during the entrainment to PV-IN firing patterns recorded in awake, behaving mice in vivo. However, prolonged, high-frequency activity during evoked trains of APs and during seizure-like events resulted in changes in the waveform of the axonal (but not somatic) AP, at least in part due to intrinsic use-dependent mechanisms. This use-dependent decrement in the axonal AP waveform is associated with decreases in calcium influx at PV-IN boutons and subsequent PV-IN-mediated synaptic transmission, indicating this phenomenon may lead to a dissociation between somatic and axonal excitability that could shape PV-IN contributions to circuit dynamics during periods of high activity.

neuroscience↗

bioRxiv2024

Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy

The recurrent pathogenic variant KCNC1-p.Ala421Val (A421V) is a cause of developmental and epileptic encephalopathy characterized by moderate-to-severe developmental delay/intellectual disability, and infantile-onset treatment-resistant epilepsy with multiple seizure types including myoclonic seizures. Yet, the mechanistic basis of this disease, and of the KCNC1 disease spectrum, is unclear. KCNC1 encodes Kv3.1, a voltage-gated potassium channel subunit that is highly and selectively expressed in neurons capable of generating action potentials at high frequency, including parvalbumin-positive fast-spiking GABAergic inhibitory interneurons in cerebral cortex (PV-INs) known to be important for cognitive function and plasticity as well as control of network excitation to prevent seizures. In this study, we generate a novel transgenic mouse model with conditional expression of the Ala421Val pathogenic missense variant (Kcnc1-A421V/+ mice) to explore the specific physiological mechanisms of KCNC1 developmental and epileptic encephalopathy. Our results indicate that global heterozygous expression of the A421V variant leads to cognitive impairment, epilepsy, and premature lethality. We observe decreased PV-IN cell surface expression of Kv3.1 via immunohistochemistry, decreased voltage-gated potassium current density in PV-INs using outside-out nucleated macropatch recordings in brain slice, and profound impairments in the intrinsic excitability of cerebral cortex PV-INs (but not excitatory neurons) in current-clamp electrophysiology. In vivo two-photon calcium imaging revealed altered basal activity in Kcnc1-A421V/+ PV-INs and excitatory cells, as well as hypersynchronous discharges correlated with brief paroxysmal movements that were subsequently shown to be myoclonic seizures on electroencephalography. We found alterations in PV-IN-mediated inhibitory neurotransmission in young adult but not juvenile Kcnc1-A421V/+ mice relative to wild-type controls. Together, these results establish the specific impact of the recurrent Kv3.1-A421V variant on neuronal excitability and synaptic physiology across development to drive network dysfunction underlying KCNC1 epileptic encephalopathy.

neuroscience↗