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.

Electrophysiological properties of genetically identified subtypes of layer 5 neocortical pyramidal neurons: Ca2+ dependence and differential modulation by norepinephrine

“…In contrast, the more excitable Glt cells had lower V th , narrower APs, greater sag, larger mAHPs, and very little sAHP. The narrower APs in glt cells reflected the higher peak dV/dt for both spike polarization and repolarization, suggesting differences between layer etv1 and glt cells in both depolarizing Na ϩ currents and repolarizing K ϩ currents (Sheets et al 2011). Glt cells also fired faster and with higher gain and exhibited almost no SFA.…”

“…We determined the laminar distribution and soma size of etv1 and glt cells. Also, because etv1 cells are reported to be a subset of IT-type neurons and glt cells a subset of PT-type neurons, we examined whether reported electrophysiological differences between PT and IT-type cells [in R in , AP width, spike frequency adaptation (SFA), and hyperpolarization-activated cation current (I H ); e.g., Christophe et al 2005;Dembrow et al 2010;Gee et al 2012;Hattox and Nelson 2007;Le Be et al 2007;Sheets et al 2011;Solomon et al 1993] might also be characteristic of glt and etv1 cells.…”

“…; Schwindt et al 1997;Sheets et al 2011;Suter et al 2013). Slender-tufted callosal-projecting neurons (IT-type) have high R in and V th , broad APs, pronounced sAHP, slower firing with lower gain, and pronounced SFA (Avesar and Gulledge 2012;Brown and Hestrin 2009;Dembrow et al 2010;Hattox and Nelson 2007;Le Be et al 2007;Schwindt et al 1997;Sheets et al 2011;Suter et al 2013).…”

“…Slender-tufted callosal-projecting neurons (IT-type) have high R in and V th , broad APs, pronounced sAHP, slower firing with lower gain, and pronounced SFA (Avesar and Gulledge 2012;Brown and Hestrin 2009;Dembrow et al 2010;Hattox and Nelson 2007;Le Be et al 2007;Schwindt et al 1997;Sheets et al 2011;Suter et al 2013). Thick-tufted neurons projecting to the brainstem or spinal cord also have larger and faster I H (and correspondingly more pronounced voltage sag in current clamp) than callosal-projecting (or contralateral striatal-projecting) neurons (Brown and Hestrin 2009;Christophe et al 2005;Dembrow et al 2010;Gee et al 2012;Solomon et al 1993;Sheets et al 2011).…”

Control of layer 5 pyramidal cell spiking by oscillatory inhibition in the distal apical dendrites: a computational modeling study

“…If these are synchronous among somatostatin-expressing neurons, the resonance that we describe might be involved in controlling the gain of the distal dendrites during quiet wakefulness, which would fluctuate in a complex manner. It is also of interest that, in the motor cortex, layer 5B, corticospinal pyramidal neurons have significantly larger I h than in other layer 5 pyramidal cells (Sheets et al 2011). Coherent beta activity in the motor cortex and the muscles is known to diminish or disappear during motor preparation and execution (Baker et al 1997;Tzagarakis et al 2010), appearing more prominently when at rest or during steady contractions following a movement (Baker 2007).…”