title: Corticospinal-specific HCN expression in mouse motor cortex: I(h)-dependent synaptic integration as a candidate microcircuit mechanism involved in motor control.
abstract: Motor cortex is a key brain center involved in motor control in rodents and other mammals, but specific intracortical mechanisms at the microcircuit level are largely unknown. Neuronal expression of hyperpolarization-activated current (I(h)) is cell class specific throughout the nervous system, but in neocortex, where pyramidal neurons are classified in various ways, a systematic pattern of expression has not been identified. We tested whether I(h) is differentially expressed among projection classes of pyramidal neurons in mouse motor cortex. I(h) expression was high in corticospinal neurons and low in corticostriatal and corticocortical neurons, a pattern mirrored by mRNA levels for HCN1 and Trip8b subunits. Optical mapping experiments showed that I(h) attenuated glutamatergic responses evoked across the apical and basal dendritic arbors of corticospinal but not corticostriatal neurons. Due to I(h), corticospinal neurons resonated, with a broad peak at ∼4 Hz, and were selectively modulated by α-adrenergic stimulation. I(h) reduced the summation of short trains of artificial excitatory postsynaptic potentials (EPSPs) injected at the soma, and similar effects were observed for short trains of actual EPSPs evoked from layer 2/3 neurons. I(h) narrowed the coincidence detection window for EPSPs arriving from separate layer 2/3 inputs, indicating that the dampening effect of I(h) extended to spatially disperse inputs. To test the role of corticospinal I(h) in transforming EPSPs into action potentials, we transfected layer 2/3 pyramidal neurons with channelrhodopsin-2 and used rapid photostimulation across multiple sites to synaptically drive spiking activity in postsynaptic neurons. Blocking I(h) increased layer 2/3-driven spiking in corticospinal but not corticostriatal neurons. Our results imply that I(h)-dependent synaptic integration in corticospinal neurons constitutes an intracortical control mechanism, regulating the efficacy with which local activity in motor cortex is transferred to downstream circuits in the spinal cord. We speculate that modulation of I(h) in corticospinal neurons could provide a microcircuit-level mechanism involved in translating action planning into action execution.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. p-sheets@northwestern.edu
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Sheets
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Suter
authors.forename: Taro
authors.initials: T
authors.lastname: Kiritani
authors.forename: C Savio
authors.initials: CS
authors.lastname: Chan
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
authors.forename: Gordon M G
authors.initials: GM
authors.lastname: Shepherd
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D003337:Corpus Callosum / Q000166:cytology / Q000502:physiology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D003712:Dendrites / Q000502:physiology; D004525:Efferent Pathways / Q000166:cytology / Q000502:physiology*; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009044:Motor Cortex / Q000166:cytology / Q000502:physiology*; D009924:Organ Culture Techniques; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology; D011712:Pyramidal Tracts / Q000166:cytology / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000502:physiology; D013569:Synapses / Q000502:physiology
chemical_list: D000322:Adrenergic Agonists; D054815:Cyclic Nucleotide-Gated Cation Channels; C578666:Hcn1 protein, mouse; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008565:Membrane Proteins; C523657:Pex5l protein, rat; D015221:Potassium Channels; D011743:Pyrimidines; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; C082246:ICI D2788; D018698:Glutamic Acid