Resurgent Na+ currents promote ultrafast spiking in projection neurons that drive fine motor control

Abstract

The underlying mechanisms that promote precise spiking in upper motor neurons controlling fine motor skills are not well understood. Here we report that projection neurons in the adult zebra finch song nucleus RA display robust high-frequency firing, ultra-narrow spike waveforms, superfast Na+ current inactivation kinetics, and large resurgent Na+ currents (INaR). These properties of songbird pallial motor neurons closely resemble those of specialized large pyramidal neurons in mammalian primary motor cortex. They emerge during the early phases of song development in males, but not females, coinciding with a complete switch of Na+ channel subunit expression from Navβ3 to Navβ4. Dynamic clamping and dialysis of Navβ4’s C-terminal peptide into juvenile RA neurons provide evidence that Navβ4, and its associated INaR, promote neuronal excitability. We thus propose that INaR modulates the excitability of upper motor neurons that are required for the execution of fine motor skills.

Emergence of sex-specific transcriptomes in a sexually dimorphic brain nucleus

“…To validate the DEG analysis, we compared our results with published mRNA and protein expression patterns in the RA, focusing on the relative trends for each gene, and found consistent sex differences and developmental changes for SCN3B and SCN4B, which are associated with sex differences in key excitable properties of RA projection neurons ( Zemel et al, 2021 ). We also found consistent sex differences and/or developmental changes for SCAMP1 ( Tang and Wade, 2011 ), VIM ( Tang and Wade, 2016 ), PVALB ( Braun et al, 1991 ), ROBO1 and SLIT1 ( Wang et al, 2015b ), and GAP43/NEUM ( Clayton et al, 2009 ).…”

“…CACNA1E codes for an R-type voltage-gated calcium channel that limits depolarization in mammalian hippocampus ( Bloodgood and Sabatini, 2007 ; Wang et al, 2015a ). This raises the possibility that developmental downregulation of CACNA1E in males contributes to the male-specific increases in action potential amplitude observed in developing RA neurons ( Zemel et al, 2021 ).…”

“…In line with a role for sex steroids in song system masculinization, males expressed higher levels of genes encoding sex steroid metabolism and biosynthesis enzymes (e.g., HSD17B4, HSDL2, SRD5A2). Many voltage-gated ion channel genes were female biased at 50 DPH, largely due to developmental decreases in males; however, some genes exhibited large male-specific developmental increases, including SCN4B, which is associated with the developmental emergence of large sex differences in resurgent sodium current and spiking rates of RA projection neurons ( Zemel et al, 2021 ).…”

“…Arrows denote ages used to generate RNA-seq data for this study; for the corresponding Nissl images, see Figure S1 . Information summarized from Adret and Margoliash (2002) , Bottjer et al (1985 , 1986) , Burek et al (1994) , Kirn and DeVoogd (1989) , Konishi and Akutagawa (1985 , 1987 ), Mooney and Rao (1994) , Nixdorf-Bergweiler (1996) , Nordeen and Nordeen (1988a , 1988b ), Nordeen et al (1992) , Ölveczky et al (2011) , Zemel et al (2021) .…”

“…Due to these cellular changes, the adult male RA is characterized by more numerous, large, widely spaced cells, and the adult female RA is characterized by fewer, small, tightly packed cells ( Figure 1B ). In tandem with morphological dimorphism, the RA develops sex differences in innervation from afferents ( Burek et al, 1994 ; Konishi and Akutagawa, 1985 ; Mooney and Rao, 1994 ; Nordeen and Nordeen, 1988a ; Nordeen et al, 1992 ), cell survival ( Kirn and DeVoogd, 1989 ), and excitability properties ( Adret and Margoliash, 2002 ; Ölveczky et al, 2011 ; Zemel et al, 2021 ) (summarized in Figure 1C ). In addition, developmental sex differences in expression levels have been characterized for several genes in the RA ( Nevue et al, 2020 ; Tang and Wade, 2011 ; Wade et al, 2005 ; Wang et al, 2015b ; Wild et al, 2001 ).…”