Biology subjects

Leiva-Salcedo, E.

Publications and source records attributed to Leiva-Salcedo, E..

3 recordsLinked to original sources

bioRxiv2026

Enhanced Ba2+-sensitive inward rectifying potassium conductance reduces intrinsic excitability of layer 2/3 pyramidal neurons in the primary auditory cortex of Fmr1 knockout mice

Fragile X syndrome (FXS) is frequently associated with auditory hypersensitivity and altered cortical processing, yet the intrinsic ionic mechanisms shaping auditory cortex excitability remain incompletely defined. Here, we tested whether subthreshold conductances contribute to compensatory changes in intrinsic excitability in layer 2/3 (L2/3) pyramidal neurons of the primary auditory cortex (AC) in Fmr1 knockout (Fmr1-KO) mice. We performed wholecell patchclamp recordings in acute slices from juvenile mice (P28-P42) and quantified passive properties, firing output, synaptic potentials, and subthreshold currents under pharmacological isolation. Compared with wild type (WT), Fmr1-KO L2/3 neurons displayed a more hyperpolarized resting membrane potential, reduced input resistance, elevated rheobase, prolonged firstspike latency, and reduced firing across depolarizing steps, consistent with a hypoexcitable state. Bath application of BaCl2 (60 M) depolarized the membrane, increased input resistance, and restored firing output and rheobase toward WT levels, indicating that a Ba2+-sensitive potassium conductance strongly constrains excitability in Fmr1-KO neurons. Voltageclamp recordings revealed a larger Ba2+-sensitive inwardly rectifying (Kir-like) current in Fmr1-KO neurons, supporting increased functional Ba2+-sensitive inwardly rectifying conductance. In contrast, blocking Ih with ZD7288 (10 M) produced modest changes in passive properties but induced genotype dependent effects on excitability and enhanced synaptic activity and EPSP summation preferentially in Fmr1-KO neurons, consistent with a role for Ih in input filtering rather than setting basal conductance. Together, these findings identify enhanced Ba2+-sensitive potassium conductance as a primary determinant of the Fmr1-KO subthreshold conductance state in AC L2/3 pyramidal neurons, suggesting an intrinsic homeostatic mechanism that stabilizes output in the presence of elevated excitatory drive.

neuroscience↗

bioRxiv2026

Subthreshold Kir and Ih currents modulate excitability of Layer 1 VIP interneurons in the medial prefrontal cortex

Cortical layer 1 (L1) is a key site for integrating top-down and bottom-up information and is populated by inhibitory interneurons, including vasoactive intestinal peptide (VIP)-expressing cells. These interneurons regulate information flow across the cortical column by disinhibiting pyramidal neurons, yet the subthreshold ionic mechanisms that shape their excitability in the medial prefrontal cortex (mPFC) remain poorly understood. Here, we characterize the electrophysiological properties of L1b VIP interneurons in mouse mPFC, focusing on the role of the hyperpolarization-activated cation current (Ih) and inward-rectifying potassium current (Kir). Using whole-cell recordings in acute slices, we find that L1b VIP interneurons exhibit constitutively active Ih and Kir conductances. Inhibition of Ih with ZD-7288 hyperpolarized the resting membrane potential (RMP), increased input resistance (Rin), and prolonged action potential (AP) duration without altering rheobase or firing frequency, while increasing EPSP-spike coupling probability. Blocking Kir with BaCl2 depolarized the RMP, increased Rin and membrane time constant, reduced rheobase, increased firing frequency, and similarly enhanced EPSP-spike probability and AP duration. Voltage-clamp experiments confirmed the presence of ZD-7288-sensitive Ih and BaCl2-sensitive Kir currents of small amplitude but operating on a high-resistance membrane, consistent with a strong impact on excitability. In contrast, neither Ih nor Kir inhibition affected the amplitude or frequency of spontaneous or miniature EPSCs, indicating that these currents do not measurably alter basal excitatory synaptic transmission. Immunofluorescence revealed weak somatic HCN1 and no detectable HCN2 expression in L1b VIP interneurons. Notably, Kir inhibition unmasked an Ih-dependent voltage sag during hyperpolarizing steps, suggesting that constitutive Kir activity normally masks Ih recruitment at subthreshold potentials. Together, these results indicate that Ih and Kir are active near RMP in L1b VIP interneurons and jointly regulate their passive properties, intrinsic excitability, and EPSP-spike coupling, therefore shaping how L1 VIP cells filter incoming signals and influence information flow within the prefrontal cortical column.

neuroscience↗

bioRxiv2024

A KCNC1 Variant Linked to Rett Syndrome Disrupts ER to Golgi Trafficking of Kv3.1 Channel

Intrinsic neuronal excitability, defined by the balance between input and output signals, is crucial to neural function, and its disruption underlies various neurological diseases. Kv3.1 channels, encoded by KCNC1, are essential for high-frequency action potential firing. Variants in these channels are associated with several subtypes of epilepsy. We report a patient with developmental regression and epilepsy, meeting Rett syndrome criteria, who carries a KCNC1 variant encoding the S474C substitution in Kv3.1 (Kv3.1S474C). Electrophysiological and biochemical assays reveal that Kv3.1S474C reduces channel presence in the plasma membrane and is retained in the endoplasmic reticulum (ER). In murine primary cultures expressing Kv3.1S474C, we observed reduced neuronal firing frequency and exclusion of the channel from the axon initial segment (AIS). Consistently, we found a decreased firing frequency using a conductance-based computational neuronal model. In summary, this study identifies a novel link between a KCNC1 variant and Rett syndrome, highlighting the importance of S474 residue in Kv3.1 channel trafficking and function in neurons. SummaryThis study identifies and characterizes a novel KCNC1 variant associated with classical Rett syndrome. This variant disrupts endoplasmic reticulum (ER) to Golgi trafficking of the Kv3.1 channels, highlighting the variants potential role in altered neuronal excitability and neurodevelopmental disorders.

cell biology↗