Biology subjects

Brager, D. H.

Publications and source records attributed to Brager, D. H..

3 recordsLinked to original sources

bioRxiv2021

High and low expression of the hyperpolarization activated current (Ih) in mouse CA1 stratum oriens interneurons.

Inhibitory interneurons are among the most diverse cell types in the brain; the hippocampus itself contains more than 28 different inhibitory interneurons. Interneurons are typically classified using a combination of physiological, morphological and biochemical observations. One broad separator is action potential firing: low threshold, regular spiking vs. higher threshold, fast spiking. We found that spike frequency adaptation (SFA) was highly heterogeneous in low threshold interneurons in the mouse stratum oriens region of area CA1. Analysis with a k-means clustering algorithm parsed the data set into two distinct clusters based on a constellation of physiological parameters and reliably sorted strong and weak SFA cells into different groups. Interneurons with strong SFA fired fewer action potentials across a range of current inputs and had lower input resistance compared to cells with weak SFA. Strong SFA cells also had higher sag and rebound in response to hyperpolarizing current injections. Morphological analysis shows no difference between the two cell types and the cell types did not segregate along the dorsal-ventral axis of the hippocampus. Strong and weak SFA cells were labeled in hippocampal slices from SST:cre Ai14 mice suggesting both cells express somatostatin. Voltage-clamp recordings showed hyperpolarization activated current Ih was significantly larger in strong SFA cells compared to weak SFA cells. We suggest that the strong SFA cell represents a previously uncharacterized type of CA1 stratum oriens interneuron. Due to the combination of physiological parameters of these cells, we will refer to them as Low Threshold High Ih (LTH) cells. Key PointsO_LISpike frequency adaptation (SFA) was highly variable among stratum oriens interneurons C_LIO_LIAdapting stratum oriens interneurons were separated into two cell groups using multiple subthreshold and action potential parameters by cluster analysis C_LIO_LICells with strong SFA fired fewer action potentials for a given current injection, had lower input resistance and more sag and rebound compared to weak SFA cells C_LIO_LIThe physiological differences were not correlated with neuron morphology, location in stratum oriens, or anatomical location along the dorsal-ventral axis of the hippocampus C_LIO_LIVoltage-clamp recordings revealed that strong SFA cells had higher density of the hyperpolarization activated current Ih compared to weak SFA cells C_LI

neuroscience↗

bioRxiv2021

Altered A-type potassium channel function impairs dendritic spike initiation and temporammonic long-term potentiation in Fragile X syndrome

Fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism spectrum disorder. Area CA1 of the hippocampus receives current information about the external world from the entorhinal cortex via the temporoammonic (TA) pathway. Given its role in learning and memory, it is surprising that little is known about TA long-term potentiation (TA-LTP) in FXS. We found that TA-LTP was impaired in fmr1 KO mice. Furthermore, dendritic Ca2+ influx was smaller and dendritic spike threshold was depolarized in fmr1 KO mice. Dendritic spike threshold and TA-LTP were restored by block of A-type K+ channels. The impairment of TA-LTP coupled with enhanced Schaffer collateral LTP may contribute to spatial memory alterations in FXS. Furthermore, as both of these LTP phenotypes are attributed to changes in A-type K+ channels in FXS, our findings provide a potential therapeutic target to treat cognitive impairments in FXS.

neuroscience↗

bioRxiv2020

Fragile X Mental Retardation Protein modulates somatic D-type K+ channels and action potential threshold in the mouse prefrontal cortex

Axo-somatic K+ channels control action potential output in part by acting in concert with voltage-gated Na+ channels to set action potential threshold. Slowly inactivating, D-type K+ channels are enriched at the axo-somatic region of cortical pyramidal neurons of the prefrontal cortex where they regulate action potential firing. We previously demonstrated that D-type K+ channels are down regulated in extratelencephalic-projecting L5 neurons (ET) in the prefrontal cortex of the fmr1 knockout mouse model of Fragile X syndrome (FX mice), resulting in a hyperpolarized action potential threshold. To test whether K+ channel alterations are regulated in a cell autonomous manner in FXS, we used a viral-mediated approach to restore expression of Fragile X Mental Retardation Protein (FMRP) in a small population of prefrontal neurons in male FX mice. Outside-out voltage clamp recordings revealed a higher D-type K+ conductance in FMRP-positive ET neurons compared to nearby FMRP-negative ET neurons. FMRP did not affect either rapidly inactivating A-type or non-inactivating K+ conductance. ET neuron patches recorded with FMRP1-298, a truncated form of FMRP which lacks mRNA binding domains, included in the pipette solution had larger D-type K+ conductance compared to heat-inactivated controls. Viral expression of FMRP in FX mice depolarized action potential threshold to near wild type levels in ET neurons. These results suggest that FMRP influences the excitability of ET neurons in the mPFC by regulating somatic D-type K+ channels in a cell autonomous, protein-protein dependent manner.

neuroscience↗