Biology subjects

Herstel, L. J.

Publications and source records attributed to Herstel, L. J..

3 recordsLinked to original sources

bioRxiv2024

Distinct modulation of Ih by synaptic potentiation in excitatory and inhibitory neurons

Selective modifications in the expression or function of dendritic ion channels regulate the propagation of synaptic inputs and determine the intrinsic excitability of a neuron. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open upon membrane hyperpolarization and conduct a depolarizing inward current (Ih). HCN channels are enriched in the dendrites of hippocampal pyramidal neurons where they regulate the integration of synaptic inputs. Synaptic plasticity can bidirectionally modify dendritic HCN channels in excitatory neurons depending on the strength of synaptic potentiation. In inhibitory neurons, however, the dendritic expression and modulation of HCN channels is largely unknown. In this study, we systematically compared the modulation of Ih by synaptic potentiation in hippocampal CA1 pyramidal neurons and stratum Radiatum (sRad) interneurons. Ih properties were similar in inhibitory and excitatory neurons and contributed to resting membrane potential and action potential firing. We found that in sRad interneurons, HCN channels were downregulated after synaptic plasticity, irrespective of the strength of synaptic potentiation. This suggest differential regulation of Ih in excitatory and inhibitory neurons, possibly signifying their distinct role in network activity. Significance statementLearning reflects a change in the way information is processed in neuronal circuits. This occurs via changes in synaptic connections and via alterations of intrinsic excitability of neurons. Here we examined how synaptic changes affect properties of HCN channels, which are important ion channels for intrinsic excitability. We found that strong synaptic potentiation leads to opposite changes in HCN channels in CA1 pyramidal neurons and sRad interneurons. We speculate that this reflects their differential role in the CA1 network. An upregulation of HCN channels in pyramidal neurons results in a decrease in their excitability, which limits overall network excitation. In contrast, sRad interneurons show downregulation of Ih, and therefore an increased excitability after strong synaptic activation, which will strengthen feedforward inhibition and sharpen activity patterns.

neuroscience↗

bioRxiv2022

Using SuperClomeleon to measure changes in intracellular chloride during development and after early life stress

Intraneuronal chloride concentrations ([Cl-]i) decrease during development resulting in a shift from depolarizing to hyperpolarizing y-aminobutyric acid (GABA) responses via chloride-permeable GABAA receptors. This GABA shift plays a pivotal role in postnatal brain development, and can be strongly influenced by early life experience. Here, we assessed the applicability of the recently developed fluorescent SuperClomeleon (SClm) sensor to examine changes in [Cl-]i using two-photon microscopy in brain slices. We used SClm mice of both sexes to monitor the developmental decrease in neuronal chloride levels in organotypic hippocampal cultures. We could discern a clear reduction in [Cl-]i between DIV3 and DIV9 (equivalent to the second postnatal week in vivo) and a further decrease in some cells until DIV22. In addition, we assessed alterations in [Cl-]i in the medial prefrontal cortex (mPFC) of P9 male SClm mouse pups after early life stress (ELS). ELS was induced by limiting nesting material between P2 and P9. ELS induced a shift towards higher (i.e. immature) chloride levels in layer 2/3 cells in the mPFC. Although conversion from SClm fluorescence to absolute chloride concentrations proved difficult, our study underscores that the SClm sensor is a powerful tool to measure physiological changes in [Cl-]i in brain slices. Significance StatementThe reduction of intraneuronal chloride concentrations is crucial for brain development, as it ensures a shift from the initial excitatory action of the neurotransmitter GABA in immature neurons to the inhibitory GABA signaling in the adult brain. Despite the significance of chloride maturation, it has been difficult to study this phenomenon in experiments. Recent development of chloride sensors enable direct imaging of intracellular chloride signaling in neurons. Here we assessed the applicability of the SuperClomeleon chloride sensor to measure physiologically relevant changes in chloride levels using two-photon microscopy in cultured and acute brain slices. Although we also point out some limitations, we conclude that the SuperClomeleon sensor is a powerful tool to measure physiological changes in intracellular chloride.

neuroscience↗

bioRxiv2020

Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Early neuronal development is a well-coordinated process in which neuronal stem cells differentiate into polarized neurons. This process has been well studied in classical non-human model systems, but to what extent this is recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured human iPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. We found extensive remodeling of the neuron transcriptome and proteome, with altered mRNA expression of ~1,100 genes and different expression profiles of ~1,500 proteins during neuronal differentiation and polarization. We also identified a distinct stage in axon development marked by an increase in microtubule remodeling and apparent relocation of the axon initial segment from the distal to proximal axon. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.

neuroscience↗