Browsing by Author "Studtmann, Carleigh"

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    Deficiency in the cell-adhesion molecule dscaml1 impairs hypothalamic CRH neuron development and perturbs normal neuroendocrine stress axis function
    Ma, Manxiu; Brunal, Alyssa A.; Clark, Kareem C.; Studtmann, Carleigh; Stebbins, Katelyn; Higashijima, Shin-ichi; Pan, Y. Albert (Frontiers, 2023-02-16)
    The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress-associated neurological and behavioral dysfunctions, it is critical to identify the mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identified Down syndrome cell adhesion molecule like-1 (dscaml1) as an integral mediator of CRH neuron development and necessary for establishing normal stress axis function. In dscaml1 mutant animals, hypothalamic CRH neurons had higher crhb (the CRH homolog in zebrafish) expression, increased cell number, and reduced cell death compared to wild-type controls. Physiologically, dscaml1 mutant animals had higher baseline stress hormone (cortisol) levels and attenuated responses to acute stressors. Together, these findings identify dscaml1 as an essential factor for stress axis development and suggest that HPA axis dysregulation may contribute to the etiology of human DSCAML1- linked neuropsychiatric disorders.
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    Diverse Mechanisms Impair Thalamic Circuit Function in a Dravet Syndrome Mouse Model
    Studtmann, Carleigh (Virginia Tech, 2022-04-06)
    Dravet syndrome (DS) is an infantile epileptic encephalopathy that is caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel, NaV1.1. Haploinsufficiency of NaV1.1 in DS patients leads to imbalanced excitability across brain circuits, resulting in a broad phenotypic profile including drug-resistant convulsive and non-convulsive (absence) seizures, cognitive impairment, ataxia, and sleep disruption. Dysfunction in the somatosensory corticothalamic (CT) circuit underlies several DS phenotypes including absence seizures and sleep disturbances. Yet, the precise mechanisms underlying somatosensory CT circuit dysfunction in DS remain unclear. Here, we sought to identify the cellular and synaptic mechanisms underlying somatosensory CT circuit dysfunction in a haploinsufficiency DS mouse model. This work reveals that NaV1.1 haploinsufficiency leads to cell-type-specific changes in the excitability of reticular thalamic (nRT), ventral posterolateral (VPL), and ventral posteromedial (VPM) neurons. Further, we identified alterations in both glutamatergic and GABAergic synaptic connectivity within the somatosensory CT circuit in DS mice. These findings introduce glutamatergic neuron dysfunction and synaptic alterations as novel disease mechanisms underlying thalamic circuit dysfunction in DS, providing new targets for therapeutic intervention. In addition, we reveal that VPL and VPM neurons exhibit distinct firing properties in a healthy CT circuit, suggesting they differentially contribute to circuit-wide function in health and dysfunction in disease.
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    NaV1.1 haploinsufficiency impairs glutamatergic and GABAergic neuron function in the thalamus
    Studtmann, Carleigh; Ladislav, Marek; Topolski, Mackenzie A.; Safari, Mona; Swanger, Sharon A. (Academic Press Inc Elsevier Science, 2022-06)
    Thalamocortical network dysfunction contributes to seizures and sleep deficits in Dravet syndrome (DS), an infantile epileptic encephalopathy, but the underlying molecular and cellular mechanisms remain elusive. DS is primarily caused by mutations in the SCN1A gene encoding the voltage-gated sodium channel Na(V)1.1, which is highly expressed in GABAergic reticular thalamus (nRT) neurons as well as glutamatergic thalamocortical neurons. We hypothesized that Na(V)1.1 haploinsufficiency alters somatosensory corticothalamic circuit function through both intrinsic and synaptic mechanisms in nRT and thalamocortical neurons. Using Scn1a heterozygous mice of both sexes aged P25-P30, we discovered reduced excitability of nRT neurons and thalamocortical neurons in the ventral posterolateral (VPL) thalamus, while thalamocortical ventral posteromedial (VPM) neurons exhibited enhanced excitability. Na(V)1.1 haploinsufficiency enhanced GABAergic synaptic input and reduced glutamatergic input to VPL neurons, but not VPM neurons. In addition, glutamatergic input to nRT neurons was reduced in Scn1a heterozygous mice. These findings introduce alterations in glutamatergic synapse function and aberrant glutamatergic neuron excitability in the thalamus as disease mechanisms in DS, which has been widely considered a disease of GABAergic neurons. This work reveals additional complexity that expands current models of thalamic dysfunction in DS and identifies new components of corticothalamic circuitry as potential therapeutic targets.