Biology subjects

Atwood, B. K.

Publications and source records attributed to Atwood, B. K..

4 recordsLinked to original sources

bioRxiv2022

Genetic Variants of Phospholipase C-γ 2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimers Disease

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimers disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and acts in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. We report the identification of a PLCG2 variant, PLCG2M28L, associated with loss-of-function and confers increased AD risk. PLCG2P522R attenuates disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbates the plaque burden associated with altered phagocytosis and A{beta} clearance. The variants bidirectionally modulate disease pathology by inducing distinct transcriptional programs that identify microglial subpopulations associated with protective or detrimental phenotypes. In summary, these findings identify PLCG2M28L as a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/519685v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@19f0aa6org.highwire.dtl.DTLVardef@74191eorg.highwire.dtl.DTLVardef@1d3a3forg.highwire.dtl.DTLVardef@db2a44_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA genetic variant of PLCG2, M28L, is associated with an increased risk for Alzheimers disease (AD) C_LIO_LIIn an amyloidogenic AD mouse model, PLCG2M28L exacerbates disease pathogenesis C_LIO_LIConversely, PLCG2P522R, a protective PLCG2 variant, attenuates AD pathogenesis C_LIO_LIThe PLCG2 variants uniquely alter the microglial transcriptome and phenotypes C_LI

neuroscience↗

bioRxiv2022

Spinophilin limits metabotropic glutamate receptor 5 scaffolding to the postsynaptic density and cell type-specifically mediates excessive grooming

BackgroundConstitutive knockout of the obsessive-compulsive disorder-associated protein, disks large associated protein 3 (SAPAP3), results in repetitive motor dysfunction, such as excessive grooming, caused by increased metabotropic glutamate receptor 5 (mGluR5) activity in striatal direct- and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively). However, MSN subtype-specific signaling mechanisms that mediate mGluR5-dependent adaptations underlying excessive grooming are not fully understood. Here, we investigate the MSN subtype-specific roles of the striatal signaling hub protein, spinophilin, in mediating repetitive motor dysfunction associated with mGluR5 function. MethodsQuantitative proteomics and immunoblotting were utilized to identify how spinophilin impacts mGluR5 phosphorylation and protein interaction changes. Plasticity and repetitive motor dysfunction associated with mGluR5 action was measured using our novel conditional spinophilin mouse model that had spinophilin knocked out from striatal dMSNs or/and iMSNs. ResultsLoss of spinophilin only in iMSNs decreased performance of a novel motor repertoire, but loss of spinophilin in either MSN subtype abrogated striatal plasticity associated with mGluR5 function and prevented excessive grooming caused by SAPAP3 knockout mice and treatment with the mGluR5-specific positive allosteric modulator (VU0360172) without impacting locomotion-relevant behavior. Biochemically, we determined spinophilins protein interaction correlates with grooming behavior and loss of spinophilin shifts mGluR5 interactions from lipid-raft associated proteins toward postsynaptic density (PSD) proteins implicated in psychiatric disorders. ConclusionsThese results identify spinophilin as a novel striatal signaling hub molecule in MSNs that cell subtype-specifically mediates behavioral, functional, and molecular adaptations associated with repetitive motor dysfunction in psychiatric disorders.

neuroscience↗

bioRxiv2021

HCN1 channels mediate mu opioid receptor long-term depression at insular cortex inputs to the dorsal striatum

Mu opioid receptors (MORs) are expressed in the dorsal striatum, a brain region that mediates goal-directed (via the dorsomedial striatum), and habitual (via the dorsolateral striatum, DLS) behaviors. Our previous work indicates that glutamate transmission is depressed when MORs are activated in the dorsal striatum, inducing MOR-mediated long-term synaptic depression (MOR-LTD) or short-term depression (MOR-STD), depending on the input. In the DLS, MOR-LTD is produced by MORs on anterior insular cortex (AIC) inputs and MOR-STD occurs at thalamic inputs, suggesting input-specific MOR plasticity mechanisms. Here, we evaluated the mechanisms of induction of MOR-LTD and MOR-STD in the DLS using pharmacology and optogenetics combined with patch clamp electrophysiology. We found that cAMP/PKA signaling and protein synthesis are necessary for MOR-LTD expression, similar to previous studies of cannabinoid-mediated LTD in DLS. MOR-STD does not utilize these same mechanisms. We also demonstrated that cannabinoid-LTD occurs at AIC inputs to DLS. However, while cannabinoid-LTD requires mTOR signaling in DLS, MOR-LTD does not. We characterized the role of presynaptic HCN1 channels in MOR-LTD induction as HCN1 channels expressed in AIC are necessary for MOR-LTD expression in the DLS. These results suggest a mechanism in which MOR activation requires HCN1 to induce MOR-LTD, suggesting a new target for pharmacological modulation of synaptic plasticity, providing new opportunities to develop novel drugs to treat alcohol and opioid use disorders. Key Points- Mu opioid receptor-mediated long-term depression at anterior insular cortex inputs to dorsolateral striatum involves presynaptic cAMP/PKA signaling and protein translation, similar to known mechanisms of cannabinoid long-term depression. - Dorsal striatal cannabinoid long-term depression also occurs at anterior insular cortex inputs to dorsolateral striatum. Dorsal striatal cannabinoid long-term depression requires mTOR signaling, similar to hippocampal cannabinoid long-term depression, but dorsal striatal mu opioid long-term depression does not require mTOR signaling. - Mu opioid long-term depression requires presynaptic HCN1 channels at anterior insular cortex inputs to dorsolateral striatum.

neuroscience↗

bioRxiv2020

Prenatal Methadone Exposure Disrupts Behavioral Development and Alters Motor Neuron Intrinsic Properties and Local Circuitry

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging. PME produced substantial impairments in offspring physical growth, activity in an open field, and sensorimotor milestone acquisition which were associated with alterations in motor neuron functioning and connectivity. The present study adds to the limited work examining PME by providing a comprehensive, translationally relevant characterization of how PME disrupts offspring development.

neuroscience↗