Biology subjects

Turner, R. W.

Publications and source records attributed to Turner, R. W..

3 recordsLinked to original sources

bioRxiv2026

Subthreshold Asynchronous States and Computations in Biophysically Detailed Populations of Neurons

Spikes are metabolically costly to generate and transmit, and spiking rates should be kept to a minimum for efficient coding. How low can the spike rate go? We show that computations and asynchronous states based on excitatory/inhibitory balance can exist without firing any spikes through self-sustaining subthreshold voltage fluctuations in networks of biophysically detailed Hodgkin-Huxley neurons. This novel subthreshold asynchronous state, which we call subthreshold voltage chaos, can be controlled for useful computation and pattern generation, also without firing spikes. Further, we identify candidate ion channels, low-voltage-activated T-Type calcium channels that provide a biophysical mechanism for this type of subthreshold computation. Our work here provides computational evidence for the existence of efficient neural circuits that can compute exclusively with subthreshold voltage dynamics.

neuroscience↗

bioRxiv2024

Ion channels that mediate calcium-dependent control of spike patterns are spatially organized across the soma in relation to a cytoskeletal assembly

A spectrin-actin cytoskeleton defines the structure of axons and expression of ion channels that support spike propagation, but it is not known how calcium and potassium channels are organized at the soma to control spike output patterns. The hippocampal pyramidal cell slow afterhyperpolarization (sAHP) is generated by a CaRyK protein complex of Cav1.3 calcium, RyR2, and IK potassium channels reflecting an ER-PM junction. Super resolution imaging and dimension reduction identified a highly organized distribution of CaRyK protein clusters aligned as rows with [~]155 nm periodicity that extended to branchpoints to form a non-rigid lattice-like structure across the soma. All CaRyK proteins proved to align and colocalize with the polygonal spectrin {beta}II cytoskeleton. The data indicate that CaRyK proteins at ER-PM junctions that contribute to the sAHP to control the pattern of spike output are distributed with high precision as functional ion channel nodes across the somatic spectrin cytoskeletal network. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=120 HEIGHT=200 SRC="FIGDIR/small/607230v4_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1a60adorg.highwire.dtl.DTLVardef@1c11894org.highwire.dtl.DTLVardef@34b50aorg.highwire.dtl.DTLVardef@59bb39_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Calcium-dependent regulation of neuronal excitability is rescued in Fragile X Syndrome by a tat-conjugated N-terminal fragment of FMRP

Fragile X Syndrome arises from the loss of Fragile X Messenger Ribonucleoprotein (FMRP) needed for normal neuronal excitability and circuit functions. Recent work revealed that FMRP contributes to mossy fiber LTP by adjusting Kv4 A-type current availability through interactions with a Cav3-Kv4 ion channel complex, yet the mechanism has not yet been defined. In this study using wild-type and Fmr1 knockout (KO) tsA-201 cells and cerebellar sections from Fmr1 KO mice, we show that FMRP associates with all subunits of the Cav3.1-Kv4.3-KChIP3 complex, and is critical to enabling calcium-dependent shifts in Kv4.3 inactivation to modulate A-type current. Specifically, upon depolarization Cav3 calcium influx activates dual specific phosphatase 1/6 (DUSP1/6) to deactivate ERK1/2 (ERK) and lower phosphorylation of Kv4.3, a signalling pathway that does not function in Fmr1 KO cells. In Fmr1 KO mouse tissue slices cerebellar granule cells exhibit a hyperexcitable response to membrane depolarizations. Either incubating Fmr1 KO cells or in vivo administration of a tat-conjugated FMRP N-terminus fragment (FMRP-N-tat) rescued Cav3-Kv4 function and granule cell excitability, with a decrease in the level of DUSP6. Together these data reveal a Cav3-activated DUSP signalling pathway critical to the function of a FMRP-Cav3-Kv4 complex that is misregulated in Fmr1 KO conditions. Moreover, FMRP-N-tat restores function of this complex to rescue calcium-dependent control of neuronal excitability as a potential therapeutic approach to alleviating the symptoms of Fragile X Syndrome. Significance StatementChanges in neuronal excitability and ion channel functions have been a focus in studies of Fragile X Syndrome. Previous work identified ion channels that are regulated by FMRP through either protein translation or direct protein-protein interactions. The current study reveals FMRP as a constitutive member of a Cav3-Kv4 complex that is required for a Cav3-DUSP-ERK signalling pathway to increase A-type current and reduce cerebellar granule cell excitability. In Fmr1 KO cells, Cav3-Kv4 function and calcium-dependent modulation of A-type current is lost, leading to a hyperexcitable state of cerebellar granule cells. Pretreating with FMRP-N-tat restores all Cav3-Kv4 function and granule cell excitability, providing support for FMRP-tat peptide treatment as a potential therapeutic strategy for Fragile X Syndrome.

neuroscience↗