Biology subjects

Brager, D. H.

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

8 recordsLinked to original sources

bioRxiv2025

CA2 neurons show abnormal responses to social stimuli in a rat model of Fragile X syndrome

Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is highly comorbid with autism spectrum disorders and can cause abnormal social behaviors. The CA2 subregion of the hippocampus is essential for social memory processing and social recognition. A social interaction induces changes in CA2 neuronal firing; however, it is unknown whether these changes are impaired in FXS models. Here, we examined CA2 activity in a rat model of Fragile X Syndrome (Fmr1 knockout rats). In Fmr1 knockout rats, we observed impaired CA2 cell responses to social stimuli, despite similar social behaviors. Further, in CA2 of Fmr1 knockout rats, we found reduced expression of oxytocin receptors and impaired whole cell responses to oxytocin. Together, these results raise the possibility that abnormal CA2 activity contributes to impaired social behavior in FXS and may suggest novel treatment targets for FXS patients. Significance statementFragile X Syndrome (FXS) is a neurodevelopmental disorder that can result in abnormal social behaviors, including social avoidance. Activity in the CA2 subregion of the hippocampus is believed to support social recognition and social cognition. Yet, the extent to which the CA2 subregion of the hippocampus is affected by FXS is poorly understood. In this study, we identified specific impairments in CA2 neuronal responses to social stimuli in a rat model of FXS. Further, we provide evidence suggesting that CA2 responses to oxytocin, a neuropeptide released during social interactions, are abnormal in FXS.

neuroscience↗

bioRxiv2025

Impaired thalamic burst firing in Fragile X syndrome

The thalamus performs a critical role in sensory processing by gating the flow of sensory information to the neocortex and directing sensory-driven behaviors; functions which are disrupted in people with autism spectrum disorders (ASD). We have identified cellular changes in thalamic neurons in a mouse model of Fragile X syndrome (FX), the leading monogenic cause of ASD, that alter how the thalamus transmits sensory information to neocortical circuits. In awake animals, thalamic relay cells gate input by shifting between two firing modes: burst and tonic. Relay cells in FX mice, however, do not shift between these modes and instead operate primarily in the tonic mode. We demonstrate that the lack of burst mode firing is caused by a shift in the voltage sensitivity for the Ca2+-dependent low threshold spike, which underlies normal burst firing.

neuroscience↗

bioRxiv2023

MiR-324-5p regulates the structure of dendritic spines and is essential for hippocampal long-term potentiation

MicroRNAs are an emerging class of synaptic regulators. These small noncoding RNAs post-transcriptionally regulate gene expression, thereby altering neuronal pathways and shaping cell-to-cell communication. Their ability to rapidly alter gene expression and target multiple pathways makes them interesting candidates in the study of synaptic plasticity. Here, we demonstrate that the proconvulsive microRNA miR-324-5p regulates excitatory synapse structure and function in the hippocampus of mice. Both Mir324 knockout (KO) and miR-324-5p antagomir treatment significantly reduce dendritic spine density in the hippocampal CA1 subregion, and Mir324 KO, but not miR-324-5p antagomir treatment, shift dendritic spine morphology, reducing the proportion of thin, "unstable" spines. Western blot and quantitative Real-Time PCR revealed changes in protein and mRNA levels for potassium channels, cytoskeletal components, and synaptic markers, including MAP2 and Kv4.2, which are essential for long-term potentiation (LTP). In line with these findings, slice electrophysiology revealed that LTP is severely impaired in Mir324 KO mice, while baseline excitatory activity remains unchanged. Overall, this study demonstrates that miR-324-5p regulates dendritic spine density, morphology, and plasticity in the hippocampus, potentially via multiple cytoskeletal and synaptic modulators.

neuroscience↗

bioRxiv2022

Higher hyperpolarization activated current (Ih) in a subpopulation of hippocampal stratum oriens CA1 interneurons in Fragile X mice.

Fragile X syndrome is the most common inherited form of intellectual disability and the leading monogenetic cause of autism. Studies in mouse models of autism spectrum disorders, including the Fmr1 knockout (FX) mouse, suggest that abnormal inhibition in hippocampal circuits contributes to behavioral phenotypes. We and others previously identified changes in multiple voltage-gated ion channels in hippocampal excitatory pyramidal neurons in FX mice. Whether the intrinsic properties of hippocampal inhibitory interneurons are altered in FX remains largely unknown. We made whole-cell current clamp recordings from three types of interneurons in stratum oriens of the hippocampus: fast-spiking (FS) cells and two classes of low threshold spiking cells, oriens-lacunosum moleculare (OLM) and low-threshold high Ih (LTH) neurons. We found that in FX mice, input resistance and action potential firing frequency were lower in LTH, but not FS or OLM, interneurons compared to wild type. Bath application of the h-channel blocker ZD7288 had a larger effect on input resistance in FX LTH cells and normalized input resistance between wild type and FX LTH cells, suggesting a greater contribution of Ih in FX LTH cells. In agreement, voltage clamp recordings showed that Ih was higher in FX LTH cells compared to wild type. Our results suggest that the intrinsic excitability of LTH inhibitory interneurons may contribute to altered inhibition in the hippocampus of FX mice. Significance statementChanges in the balance between excitation and inhibition underlie many neurodevelopmental disorders. Changes in several voltage-gated ion channels, which contribute to altered intrinsic excitability, were previously identified in excitatory hippocampal neurons in the Fmr1 mouse model of Fragile X syndrome. In this paper we use physiological and biochemical approaches to investigate the intrinsic excitability of inhibitory interneurons in hippocampal area CA1 of the Fragile X mouse. We found that higher Ih lowers the intrinsic excitability of one specific type of interneuron. This study highlights how changes to voltage-gated ion channels in specific neuronal populations may contribute to the altered excitatory/inhibitory balance in Fragile X syndrome.

neuroscience↗

bioRxiv2022

Impaired dendritic spike generation in the Fragile X prefrontal cortex is due to loss of dendritic sodium channels

Patients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na+ spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) PFC neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task-relevant sensory signals and guide motor actions. We used current clamp and outside-out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild type and Fmr1 knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild type. Analysis of voltage responses to simulated in vivo "noisy" current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared wild type. Patch clamp recordings revealed that the dendritic Na+ conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that input-output transformation is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D-type K+ and dendritic HCN-channel function is reduced in ET neurons, we suggest that the integration of information by PFC circuits is fundamentally altered in Fragile X syndrome. KEY POINTSO_LIDendritic spike threshold is depolarized in Layer 5 PFC neurons in FX mice C_LIO_LISimultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX ET neurons C_LIO_LIOutside-out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons C_LI

neuroscience↗

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.

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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↗