Jacob Hull

All Publications

• Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for<i> GNB1</i>-linked encephalopathy NEUROBIOLOGY OF DISEASE Denomme, N., Hodges, S. L., Lopez-Santiago, L., Yuan, Y., Ziobro, J. M., Minton, J., Chen, C., Chen, Y., Hull, J. M., Offord, J., Smrcka, A. V., Isom, L. L. 2025; 213: 106990

  Abstract

  Guanine nucleotide-binding protein Gβγ subunits are ubiquitous signaling molecules that interact with numerous effector proteins in neurons, including voltage-gated sodium, calcium, and potassium channels. We show that Gβγ subunits associate with voltage-gated sodium channels (Navs) in mouse brain, and co-expression of a prominent Gβγ complex, Gβ1γ2, leads to functional inhibition of brain Nav α subunit subtypes Nav1.1 and Nav1.6 in heterologous cells. Gβ1γ2 co-expression shows subtype-selective effects on Nav1.1 and Nav1.6 in the presence of Navβ1 subunit co-expression, and in response to prepulse voltage changes. De novo variants in GNB1, encoding the Gβ1 subunit, are linked to GNB1 encephalopathy (GNB1-E). Using cortical slice electrophysiology, we show that the Gnb1K78R/+ mouse model of GNB1-E has reduced spontaneous GABAergic, but not glutamatergic, transmission and decreased sodium current density in dissociated parvalbumin-expressing GABAergic interneurons. This work advances our understanding of the epileptic mechanisms present in GNB1-E, including a previously unrecognized role for Navs.

  View details for DOI 10.1016/j.nbd.2025.106990

  View details for Web of Science ID 001523278200001

  View details for PubMedID 40482731

• Rhythmic Quakes Shock the Cortical Focus Theory. Epilepsy currents Hull, J. M., Huguenard, J. R. 2025: 15357597251314673

  View details for DOI 10.1177/15357597251314673

  View details for PubMedID 40502809

  View details for PubMedCentralID PMC12149148

• The reuniens thalamus recruits recurrent excitation in the medial prefrontal cortex. Proceedings of the National Academy of Sciences of the United States of America Vantomme, G., Devienne, G., Hull, J. M., Huguenard, J. R. 2025; 122 (11): e2500321122

  Abstract

  The medial prefrontal cortex (mPFC) and hippocampus are critical for memory retrieval, decision making, and emotional regulation. While ventral CA1 (vCA1) shows direct and reciprocal connections with mPFC, dorsal CA1 (dCA1) forms indirect pathways to mPFC, notably via the thalamic reuniens nucleus (Re). Neuroanatomical tracing has documented structural connectivity of this indirect pathway through Re however, its functional operation is largely unexplored. Here, we used in vivo and in vitro electrophysiology along with optogenetics to address this question. Whole-cell patch-clamp recordings in acute mouse brain slices revealed both monosynaptic excitatory responses and disynaptic feedforward inhibition at Re-mPFC synapses. However, we also identified a prolonged excitation of mPFC by Re. These early monosynaptic and late recurrent components are in marked contrast to the primarily feedforward inhibition characteristic of thalamic inputs to the neocortex. Local field potential recordings in mPFC brain slices revealed prolonged synaptic activity throughout all cortical lamina upon Re activation, with the late excitation enhanced by blockade of parvalbumin neurons and GABAARs. In vivo Neuropixels recordings in head-fixed awake mice revealed a similar prolonged excitation of mPFC units by Re activation. In summary, Re output produces recurrent feedforward excitation within mPFC suggesting a potent amplification system in the Re-mPFC network. This may facilitate amplification of dCA1->mPFC signals for which Re acts as the primary conduit, as there is little direct connectivity. In addition, the capacity of mPFC neurons to fire bursts of action potentials in response to Re input suggests that these synapses have a high gain.

  View details for DOI 10.1073/pnas.2500321122

  View details for PubMedID 40085651

• Reuniens thalamus recruits recurrent excitation in medial prefrontal cortex. bioRxiv : the preprint server for biology Vantomme, G., Devienne, G., Hull, J. M., Huguenard, J. R. 2024

  Abstract

  Medial prefrontal cortex (mPFC) and hippocampus are critical for memory retrieval, decision making and emotional regulation. While ventral CA1 (vCA1) shows direct and reciprocal connections with mPFC, dorsal CA1 (dCA1) forms indirect pathways to mPFC, notably via the thalamic Reuniens nucleus (Re). Neuroanatomical tracing has documented structural connectivity of this indirect pathway through Re however, its functional operation is largely unexplored. Here we used in vivo and in vitro electrophysiology along with optogenetics to address this question. Whole-cell patch-clamp recordings in acute mouse brain slices revealed both monosynaptic excitatory responses and disynaptic feedforward inhibition for both Re-mPFC and Re-dCA1 pathways. However, we also identified a novel biphasic excitation of mPFC by Re, but not dCA1. These early monosynaptic and late recurrent components are in marked contrast to the primarily feedforward inhibition characteristic of thalamic inputs to neocortex. Local field potential recordings in mPFC brain slices revealed that this biphasic excitation propagates throughout all cortical lamina, with the late excitation specifically enhanced by GABAAR blockade. In vivo Neuropixels recordings in head-fixed awake mice revealed a similar biphasic excitation of mPFC units by Re activation. In summary, Re output produces recurrent feed-forward excitation within mPFC suggesting a potent amplification system in the Re-mPFC network. This may facilitate amplification of dCA1->mPFC signals for which Re acts as the primary conduit, as there is little direct connectivity. In addition, the capacity of mPFC neurons to fire bursts of action potentials in response to Re input suggests that these synapses have a high gain.The interactions between medial prefrontal cortex and hippocampus are crucial for memory formation and retrieval. Yet, it is still poorly understood how the functional connectivity of direct and indirect pathways underlies these functions. This research explores the synaptic connectivity of the indirect pathway through the Reuniens nucleus of the thalamus using electrophysiological recordings and optogenetic manipulations. The study found that Reuniens stimulation recruits recurrent and long-lasting activity in mPFC - a phenomenon not previously recorded. This recurrent activity might create a temporal window ideal for coincidence detection and be an underlying mechanism for memory formation and retrieval.

  View details for DOI 10.1101/2024.05.31.596906

  View details for PubMedID 38854099

  View details for PubMedCentralID PMC11160760

• XOB: A novel phenylalkylamine antagonist of 5-HT2A receptors and voltage-gated sodium channels. Molecular pharmacology Denomme, N., Hernandez, C. C., Bock, H. A., Ohana, R. F., Bakshi, S., Sherwood, A. M., McCorvy, J. D., Daley, P. F., Callaway, W. B., Hull, J. M., Alt, A., Isom, L. L., Cozzi, N. V. 2024

  Abstract

  Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin2A (5-HT2A) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT2A receptors and VGSCs. Towards this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT2A receptors and blocks sodium current. The new compound, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, Gq-mediated, calcium flux at 5-HT2A receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT1A, 5-HT2B, and 5-HT2C receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. Significance Statement We synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT2A receptors and voltage-gated sodium channels (VGSCs), in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.

  View details for DOI 10.1124/molpharm.123.000837

  View details for PubMedID 38821630

• Atlas of the aging mouse brain reveals white matter as vulnerable foci. Cell Hahn, O., Foltz, A. G., Atkins, M., Kedir, B., Moran-Losada, P., Guldner, I. H., Munson, C., Kern, F., Pálovics, R., Lu, N., Zhang, H., Kaur, A., Hull, J., Huguenard, J. R., Grönke, S., Lehallier, B., Partridge, L., Keller, A., Wyss-Coray, T. 2023

  Abstract

  Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glial aging was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.

  View details for DOI 10.1016/j.cell.2023.07.027

  View details for PubMedID 37591239

• A CMOS-based highly scalable flexible neural electrode interface. Science advances Zhao, E. T., Hull, J. M., Mintz Hemed, N., Uluşan, H., Bartram, J., Zhang, A., Wang, P., Pham, A., Ronchi, S., Huguenard, J. R., Hierlemann, A., Melosh, N. A. 2023; 9 (23): eadf9524

  Abstract

  Perception, thoughts, and actions are encoded by the coordinated activity of large neuronal populations spread over large areas. However, existing electrophysiological devices are limited by their scalability in capturing this cortex-wide activity. Here, we developed an electrode connector based on an ultra-conformable thin-film electrode array that self-assembles onto silicon microelectrode arrays enabling multithousand channel counts at a millimeter scale. The interconnects are formed using microfabricated electrode pads suspended by thin support arms, termed Flex2Chip. Capillary-assisted assembly drives the pads to deform toward the chip surface, and van der Waals forces maintain this deformation, establishing Ohmic contact. Flex2Chip arrays successfully measured extracellular action potentials ex vivo and resolved micrometer scale seizure propagation trajectories in epileptic mice. We find that seizure dynamics in absence epilepsy in the Scn8a+/- model do not have constant propagation trajectories.

  View details for DOI 10.1126/sciadv.adf9524

  View details for PubMedID 37285436

  View details for PubMedCentralID PMC10246892

• Heterogeneity of voltage gated sodium current density between neurons decorrelates spiking and suppresses network synchronization in Scn1b null mouse models. Scientific reports Hull, J. M., Denomme, N., Yuan, Y., Booth, V., Isom, L. L. 2023; 13 (1): 8887

  Abstract

  Voltage gated sodium channels (VGSCs) are required for action potential initiation and propagation in mammalian neurons. As with other ion channel families, VGSC density varies between neurons. Importantly, sodium current (INa) density variability is reduced in pyramidal neurons of Scn1b null mice. Scn1b encodes the VGSC beta1/ beta1B subunits, which regulate channel expression, trafficking, and voltage dependent properties. Here, we investigate how variable INa density in cortical layer 6 and subicular pyramidal neurons affects spike patterning and network synchronization. Constitutive or inducible Scn1b deletion enhances spike timing correlations between pyramidal neurons in response to fluctuating stimuli and impairs spike-triggered average current pattern diversity while preserving spike reliability. Inhibiting INa with a low concentration of tetrodotoxin similarly alters patterning without impairing reliability, with modest effects on firing rate. Computational modeling shows that broad INa density ranges confer a similarly broad spectrum of spike patterning in response to fluctuating synaptic conductances. Network coupling of neurons with high INa density variability displaces the coupling requirements for synchronization and broadens the dynamic range of activity when varying synaptic strength and network topology. Our results show that INa heterogeneity between neurons potently regulates spike pattern diversity and network synchronization, expanding VGSC roles in the nervous system.

  View details for DOI 10.1038/s41598-023-36036-0

  View details for PubMedID 37264112

• Ankyrin-G regulates forebrain connectivity and network synchronization via interaction with GABARAP MOLECULAR PSYCHIATRY Nelson, A. D., Caballero-Floran, R. N., Diaz, J., Hull, J. M., Yuan, Y., Li, J., Chen, K., Walder, K. K., Lopez-Santiago, L. F., Bennett, V., McInnis, M. G., Isom, L. L., Wang, C., Zhang, M., Jones, K. S., Jenkins, P. M. 2020; 25 (11): 2800-2817

  Abstract

  GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABAA receptor-associated protein (GABARAP) to stabilize cell surface GABAA receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

  View details for DOI 10.1038/s41380-018-0308-x

  View details for Web of Science ID 000611534000013

  View details for PubMedID 30504823

  View details for PubMedCentralID PMC6542726