Biology subjects

Swanson, G. T.

Publications and source records attributed to Swanson, G. T..

4 recordsLinked to original sources

bioRxiv2025

Wide-ranging behavioral dysfunction in two mouse models of pathological human variants in the GRIK2 kainate receptor gene

De novo variants in a subset of ionotropic glutamate receptor (iGluR) genes cause nonsyndromic neurodevelopmental disorders (NDDs) in individuals. Two recurrent variants in the kainate receptor (KAR) gene GRIK2 result in the gain-of-function (GoF) substitutions p.Ala657Thr and p.Thr660Lys in a critical pore-forming domain of the GluK2 subunit. Disorders in individuals with these variants manifest as intellectual disability, developmental delay, motor impairments, and, in the case of p.Thr660Lys, epilepsy. To explore their pathogenicity and phenotypic consequences in vivo, we generated knock-in mouse models harboring orthologous Grik2 mutations. Behavioral analyses revealed a range of developmental, motor, cognitive, and naturalistic behavior impairments in both lines, with T660K mice typically exhibiting more severe phenotypes, consistent with clinical observations in humans. GluK2(T660K) mice also display interictal EEG abnormalities and handling-induced seizures. These models establish the first in vivo platforms for dissecting the underlying mechanisms of NDDs caused by a GoF mutation in the GluK2 KAR subunit and represent crucial tools for therapeutic development. HighlightsO_LIDe novo variants in the GRIK2 kainate receptor gene cause developmental disorders C_LIO_LIWe studied knockin mouse models of pathogenic p.Ala657Thr and p.Thr660Lys variants C_LIO_LIGluK2(A657T) and GluK2(T660K) mice have deficits analogous to human disorder symptoms C_LIO_LILike their human counterparts, GluK2(T660K) but not GluK2(A657T) mice have seizures C_LIO_LIGrik2 knockin mice are key tools for interrogating underlying causes of dysfunction C_LI

neuroscience↗

bioRxiv2023

A pathogenic missense mutation in kainate receptors elevates dendritic excitability and synaptic integration through dysregulation of SK channels

Numerous rare de novo variants that cause neurodevelopmental disorders (NDDs) occur within genes encoding synaptic proteins, including ionotropic glutamate receptors (iGluRs). However, in many cases it remains unclear how damaging missense variants affect brain function. Here we determined the physiological consequences of an NDD causing missense mutation in the GRIK2 kainate receptor (KAR) gene, that results in a single amino acid change p.Ala657Thr in the GluK2 receptor subunit. We engineered the equivalent mutation in the mouse Grik2 gene, yielding a GluK2(A657T) mouse, to better understand the human disorder and determine how hippocampal neuronal function is disrupted. Synaptic KAR currents in hippocampal CA3 pyramidal neurons from heterozygous A657T mice exhibited slow decay kinetics, consistent with incorporation of the mutant subunit into functional receptors. Unexpectedly, CA3 neurons demonstrated elevated action potential spiking due to down-regulation of the small conductance Ca2+ activated K+ channel (SK), which mediates the post-spike afterhyperpolarization (AHP). The reduction in SK activity resulted in increased CA3 dendritic excitability, increased EPSP-spike coupling and lowered the threshold for the induction of LTP of the associational commissural (AC) synapses in the distal dendrites of CA3 neurons. Pharmacological inhibition of SK channels in wild-type (WT) mice increased dendritic excitability and EPSP-spike coupling, mimicking the phenotype in A657T mice and suggesting a causative role for attenuated SK activity in aberrant excitability observed in the mutant mice. These findings demonstrate that a disease-associated missense mutation in GRIK2 leads to altered signaling through neuronal KARs, pleiotropic effects on neuronal and dendritic excitability, and implicate these processes in neuropathology in patients with genetic NDDs.

neuroscience↗

bioRxiv2021

Activity-dependent Golgi satellite formation in dendrites reshapes the neuronal surface glycoproteome

Activity-driven changes in the neuronal surface glycoproteome are known to occur with synapse formation, plasticity and related diseases, but their mechanistic basis and significance are unclear. Here, we observed that N-glycans on surface glycoproteins of dendrites shift from immature to mature forms containing sialic acid in response to increased neuronal excitation. In exploring the basis of these N-glycosylation alterations, we discovered they result from the growth and proliferation of Golgi satellites scattered throughout the dendrite. Golgi satellites that formed with neuronal excitation were in close association with ER exit sites and early endosomes and contained glycosylation machinery without the Golgi structural protein, GM130. They functioned as distal glycosylation stations in dendrites, terminally modifying sugars either on newly synthesized glycoproteins passing through the secretory pathway, or on surface glycoproteins taken up from the endocytic pathway. These activities led to major changes in the dendritic surface of excited neurons, impacting binding and uptake of lectins, as well as causing functional changes in neurotransmitter receptors such as nicotinic acetylcholine receptors. Neural activity thus boosts the activity of the dendrites satellite micro-secretory system by redistributing Golgi enzymes involved in glycan modifications into peripheral Golgi satellites. This remodeling of the neuronal surface has potential significance for synaptic plasticity, addiction and disease.

neuroscience↗

bioRxiv2020

Enhanced synaptic transmission in the extended amygdala and altered excitability in an extended amygdala to brainstem circuit in a Dravet syndrome mouse model

ObjectiveDravet syndrome (DS) is a severe, early-onset epilepsy with an increased incidence of sudden death. Evidence of interictal breathing deficits in DS suggest that alterations in subcortical projections to brainstem nuclei may exist, which might be driving comorbidities in DS. The aim of this study was to determine if a subcortical structure, the bed nucleus of the stria terminalis (BNST) in the extended amygdala, is activated by seizures, exhibits changes in excitability, and expresses any alterations in neurons projecting to a brainstem nucleus associated with respiration, stress response and homeostasis. MethodsExperiments were conducted using F1 mice generated by breeding 129.Scn1a+/- mice with wildtype C57BL/6J mice. Immunohistochemistry was performed to quantify neuronal c-fos activation in DS mice after observed spontaneous seizures. Whole cell patch clamp and current clamp electrophysiology recordings were conducted to evaluate changes in intrinsic and synaptic excitability in the BNST. ResultsSpontaneous seizures in DS mice significantly enhanced neuronal c-fos expression in the BNST. Further, the BNST had altered AMPA/NMDA postsynaptic receptor composition and showed changes in spontaneous neurotransmission, with greater excitation and decreased inhibition. BNST to parabrachial nucleus (PBN) projection neurons exhibited intrinsic excitability in wildtype mice, while these projection neurons were hypoexcitable in DS mice. SignificanceThe findings suggest that there is altered excitability in neurons of the BNST, including BNST to PBN projection neurons, in DS mice. These alterations could potentially be driving comorbid aspects of DS outside of seizures, including respiratory dysfunction and sudden death. SIGNIFICANCE STATEMENTDravet syndrome (DS) is an early-onset epilepsy with an increased risk of sudden death. We determined that there are alterations in a subcortical nucleus, the bed nucleus of the stria terminalis (BNST) of the extended amygdala, in a murine DS model. The BNST is involved in stress, anxiety, feeding, and respiratory function. We found enhanced activation in the BNST after seizures and alterations in basal synaptic neurotransmission-with enhanced spontaneous excitatory and decreased spontaneous inhibitory postsynaptic events. Evaluating those neurons that project to the parabrachial nucleus (PBN), a nucleus with multiple homeostatic roles, we found them to be hypoexcitable in DS. Alterations in BNST to brainstem projections could be implicated in comorbid aspects of DS, including respiratory dysfunction and sudden death.

neuroscience↗