Activity-dependent ectopic action potentials in regular-spiking neurons of the neocortex

Zhang, Yizhen Z.; Sapantzi, Stella; Lin, Alice; Doelfel, Savannah R.; Connors, Barry W.; Theyel, Brian B.

doi:10.3389/fncel.2023.1267687

“…Distal axons of excitatory pyramidal neurons in hippocampal areas CA1 and CA3, for instance, initiate action potentials linked to sharp-wave ripple complexes and gamma rhythms; these may be triggered in distal axons by a GABA A receptor-mediated mechanism ( Papatheodoropoulos, 2008 ; Bahner et al, 2011 ; Dugladze et al, 2012 ). Pyramidal neurons of the mouse neocortex can generate relatively sparse EAPs following stimulation of their somata ( Zhang et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Activity-Dependent Ectopic Spiking in Parvalbumin-Expressing Interneurons of the Neocortex

Theyel,

Stevenson,

Connors

2024

eNeuro

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Canonically, action potentials of most mammalian neurons initiate at the axon initial segment and propagate bidirectionally: orthodromically along the distal axon, and retrogradely into the soma and dendrites. Under some circumstances action potentials may initiate ectopically, at sites distal to the axon initial segment, and propagate antidromically along the axon. These ‘ectopic action potentials’ (EAPs) have been observed in experimental models of seizures and chronic pain, and more rarely in nonpathological forebrain neurons. Here we report that a large majority of parvalbumin-expressing (PV+) interneurons in upper layers of mouse neocortex, from both orbitofrontal and primary somatosensory areas, fire EAPs after sufficient activation of their somata. Somatostatin-expressing interneurons also fire EAPs, though less robustly. Ectopic firing in PV+ cells occurs in varying temporal patterns and can persist for several seconds. PV+ cells evoke strong synaptic inhibition in pyramidal neurons and interneurons and play critical roles in cortical function. Our results suggest that ectopic spiking of PV+ interneurons is common, and may contribute to both normal and pathological network functions of the neocortex.Significance StatementA form of neuronal firing that emerges in distal axons and terminals – the ‘ectopic action potential’ (EAP) – has been detected in a few cell populations of the cerebral cortex. Previous investigations of parvalbumin-positive interneurons in neocortex had suggested only a small percentage of cells can fire EAPs. We found that a large fraction of parvalbumin-positive interneurons in the superficial layers of neocortex, including first-order and higher-order areas, can fire EAPs. These results broaden our understanding of the intrinsic firing characteristics of these critically important inhibitory interneurons.

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“…Distal axons of excitatory pyramidal neurons in hippocampal areas CA1 and CA3, for instance, initiate action potentials linked to sharp waveripple complexes and gamma rhythms; these may be triggered in distal axons by a GABAA receptor-mediated mechanism (Papatheodoropoulos, 2008;Bahner et al, 2011;Dugladze et al, 2012). Pyramidal neurons of the mouse neocortex can generate relatively sparse EAPs following stimulation of their somata (Zhang et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Activity-Dependent Ectopic Spiking in Parvalbumin-Expressing Interneurons of the Neocortex

Theyel,

Stevenson,

Connors

2024

Preprint

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Canonically, action potentials of most mammalian neurons initiate at the axon initial segment and propagate bidirectionally: orthodromically along the distal axon, and retrogradely into the soma and dendrites. Under some circumstances action potentials may initiate ectopically, at sites distal to the axon initial segment, and propagate antidromically along the axon. These ectopic action potentials (EAPs) have been observed in experimental models of seizures and chronic pain, and more rarely in nonpathological forebrain neurons. Here we report that a large majority of parvalbumin-expressing (PV+) interneurons in upper layers of mouse neocortex, from both orbitofrontal and primary somatosensory areas, fire EAPs after sufficient activation of their somata. Somatostatin-expressing interneurons also fire EAPs, though less robustly. Ectopic firing in PV+ cells occurs in varying temporal patterns and can persist for several seconds. PV+ cells evoke strong synaptic inhibition in pyramidal neurons and interneurons and play critical roles in cortical function. Our results suggest that ectopic spiking of PV+ interneurons is common, and may contribute to both normal and pathological network functions of the neocortex.

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Attenuated ectopic action potential firing in parvalbumin expressing interneurons in a mouse model of Dravet Syndrome

Hill,

Wengert,

Goldberg

et al. 2024

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Dravet syndrome is caused by heterozygous loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel Nav1.1. Our recent work suggests that a primary pathogenic mechanism of Dravet syndrome is impaired action potential propagation along axons of cortical parvalbumin-positive fast-spiking GABAergic interneurons (PVINs). Ectopic action potentials (EAPs) are action potentials that initiate distal to the axon initial segment. We recently demonstrated that a large proportion of PVINs fire EAPs during periods of increased excitation. Although their function remains unknown, EAPs may play a role in amplifying (when occurring in excitatory cells) and/or preventing seizures (when occurring in interneurons). Regardless of function, their generation in distal axons suggests that EAP frequency could be a useful proxy for distal axonal excitability. We hypothesized that EAPs are attenuated in PVINs from Dravet syndrome (Scn1a+/-) mice due to dysfunction of the distal axon. We induced EAPs in PVINs in acute brain slices prepared from male and female wildtype (WT) and Scn1a+/- mice at P18-21 and P35-56, when we have previously identified axonal conduction deficits in Scn1a+/- PVINs. We elicited EAPs in 17/22 (77%) of WT PVINs, including 6 (22%) that exhibited barrages of EAPs. In contrast, Scn1a+/- PVINs never fired barrages (0%), and only 8/23 (34%) exhibited even single EAPs. This finding adds to the body of evidence supporting impaired action potential propagation in Dravet syndrome PVINs, and is the first evidence of impaired EAP firing in a disease model, suggesting that dysregulation of EAPs could be involved in the pathophysiology of human disease.

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Activity-dependent ectopic action potentials in regular-spiking neurons of the neocortex

Cited by 3 publications

References 56 publications

Activity-Dependent Ectopic Spiking in Parvalbumin-Expressing Interneurons of the Neocortex

Activity-Dependent Ectopic Spiking in Parvalbumin-Expressing Interneurons of the Neocortex

Activity-Dependent Ectopic Spiking in Parvalbumin-Expressing Interneurons of the Neocortex

Attenuated ectopic action potential firing in parvalbumin expressing interneurons in a mouse model of Dravet Syndrome

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