Biology subjects

Raab-Graham, K. F.

Publications and source records attributed to Raab-Graham, K. F..

7 recordsLinked to original sources

bioRxiv2026

Granulocyte colony-stimulating factor acts through calcium-permeable AMPA receptors to potentiate cocaine reward

Neuroimmune interactions have emerged as critical modulators of substance use disorders and may represent promising translational therapeutic targets. In prior work, we demonstrated that the cytokine granulocyte colony stimulating factor (G-CSF) is elevated in mice following cocaine exposure, with circulating levels correlating with cocaine intake and locomotor sensitization. Additionally, exogenous G-CSF enhances cocaine reward and increases low-dose cocaine self-administration. We have further shown that repeated G-CSF administration alters expression of glutamatergic synapse-associated proteins following cocaine-seeking behavior. Building on these findings, the present studies examined the molecular consequences of repeated administration of G-CSF, cocaine, or their combination, with a focus on glutamatergic signaling pathways. We also tested whether altered glutamate receptor expression contributes to G-CSF-mediated enhancement of cocaine reward. Repeated combined administration of G-CSF and cocaine produced robust changes in glutamate-associated and synapse-related protein expression within the nucleus accumbens and medial prefrontal cortex. These molecular adaptations were accompanied by increased synaptic density in the nucleus accumbens. Finally, pharmacological inhibition of calcium-permeable AMPA receptors within the nucleus accumbens reversed the G-CSF-induced enhancement of cocaine conditioned place preference. Together, these findings indicate that G-CSF enhances cocaine reward at least in part by promoting glutamatergic synaptic remodeling in the nucleus accumbens, identifying a neuroimmune-glutamate mechanism that may be leveraged for therapeutic intervention.

neuroscience↗

bioRxiv2025

17β-estradiol status alters NMDAR function and antipsychotic-like activity in female rats

Low 17{beta}-estradiol (E2) in females of reproductive age, and marked E2 decline with menopause, contributes to heightened symptom severity in schizophrenia (i.e. cognitive dysfunction) and diminished response to antipsychotic medications. However, the underlying mechanisms are unknown. N-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia, yet impact of E2 depletion on NMDAR function is not well characterized. Quantitative electroencephalography (qEEG), specifically gamma power, is a well-established functional readout of cortical activity that is elevated in patients with schizophrenia and is sensitive to alterations in NMDAR function. Using qEEG and touchscreen cognitive assessments, present studies investigated the effects of E2 on NMDAR function by administering MK-801 (NMDAR antagonist) to ovariectomized rats with or without E2 implants (Ovx+E and Ovx, respectively). Ovx rats were more sensitive to MK-801-induced elevations in gamma power and attentional impairments compared to Ovx+E rats. Further investigation revealed these effects were mediated by reduced synaptic GluN2A expression. Consistent with clinical reports, olanzapine (second-generation antipsychotic) was less effective in mitigating MK-801-induced elevations in gamma power in Ovx rats. Lastly, we examined antipsychotic-like activity of a Group II metabotropic glutamate receptor (mGlu2/3) positive allosteric modulator (PAM), SBI-0646535, as a novel therapeutic in E2-deprived conditions. SBI-0646535 reversed MK-801-induced elevations in gamma power equally regardless of E2 status. Collectively, these studies established a relationship between E2 deprivation and NMDAR function that is in part GluN2A-dependent, supporting the notion that E2 deprivation increases susceptibility to NMDAR hypofunction. This highlights the need to examine age/hormone-specific factors when considering antipsychotic response and designing novel pharmacotherapies.

animal behavior and cognition↗

bioRxiv2020

Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in tuberous sclerosis complex and Alzheimer's disease

L-type voltage-dependent Ca2+ channels (L-VDCC) integrate synaptic signals to facilitate a plethora of cellular mechanisms. L-VDCC dysfunction is implicated in several neurological and psychiatric diseases. Despite their importance, signals upstream of L-VDCC activity that regulate their channel density, however, are poorly defined. In disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), including tuberous sclerosis (TS) and Alzheimers disease (AD), we report a novel mechanism downstream of mTORC1 signaling that results in a deficit in dendritic L-VDCC activity. Deficits in L-VDCC activity are associated with increased expression of the mTORC1-regulated RNA-binding protein DJ-1. DJ-1 binds the mRNA coding the auxiliary Ca2+ channel subunit 2{delta}2 responsible for shuttling L-VDCC to the membrane and represses its expression. Moreover, this novel DJ-1/2{delta}2/L-VDCC pathway is disrupted in human AD and preclinical models of AD and TS. Our discovery that DJ-1 directs L-VDCC activity and L-VDCC-associated protein 2{delta}2 at the synapse suggests that DJ-1/2{delta}2/L-VDCC is a common, fundamental pathway disrupted in TS and AD that can be targeted in clinical mTORopathies. Significance StatementMany neurological disorders share symptoms, despite disparity among diseases. Treatments are prescribed based on diagnosis rather than individual symptoms. While only treating symptoms may obscure the disease, mechanism-based drug development allows the two approaches to converge. Hub proteins, those that coordinate the expression of proteins that mediate specific cellular functions, may be dysregulated across a broad range of disorders. Herein, we show that the RNA-binding protein DJ-1 controls the activity of L-type voltage-dependent calcium channels (L-VDCC), via the expression of its auxiliary subunit alpha2delta2 (2{delta}2). Importantly, we demonstrate that this novel DJ-1/2{delta}2/L-VDCC pathway is commonly disrupted among neurological disorders, namely Alzheimers disease (AD) and Tuberous Sclerosis (TS). Collectively, these data rationalize mechanism-based drug therapy to treat disease.

neuroscience↗

bioRxiv2020

Boosting L-type Ca2+ channel activity in tuberous sclerosis mitigates excess glutamate receptors and seizures

Tuberous sclerosis complex (TS) is a dominant, multisystem disorder with devastating neurological symptoms. Approximately 85% of TS patients suffer from epilepsy over their lifespan and roughly 25-50% of those patients develop Autism Spectrum Disorder (1, 2). Current seizure therapies are effective in some, but not all, and often have significant risk factors associated with their use (1, 3). Thus, there is a critical need for new medication development or drug repositioning. Herein, we leveraged proteomic signatures of epilepsy and ASD, often comorbid in TS, to utilize an in silco approach to identify new drug therapies for TS-related seizures. We have discovered that activation of L-type voltage dependent calcium channels (L-VDCC) by Bay-K8644 (BayK) in a preclinical mouse model of TS rescues the excess expression of ionotropic, AMPA-subtype glutamate (GluA) receptors. As added proof of BayK working through L-VDCC to regulate GluA levels, we found that increasing expression of alpha2delta2 (2{delta}2), an auxiliary calcium channel subunit that boosts L-VDCC surface expression, similarly lowers the surface expression of dendritic GluA in TS. These BayK-induced molecular alterations may potentially improve the quality of life of humans suffering from TS. Significance StatementCausal mechanisms of Tuberous Sclerosis (TS)-associated neurological disorders are under-characterized and treatment options are lacking. Using a computational approach of mTOR/DJ-1 target mRNAs to predict new medications, we report that boosting L-type voltage-dependent Ca2+ channel (L-VDCC) activity in a preclinical TS mouse model that exhibits a deficit in dendritic L-VDCC activity ameliorates key molecular pathologies that are predicted to underlie seizures. Restoring the mTOR/DJ-1 pathway upstream of L-VDCC, therefore, may serve as a new therapeutic avenue to mitigate seizures and mortality in TS.

neuroscience↗

bioRxiv2020

Titrating synapse number to treat MDD in Fragile X Syndrome

Rapid antidepressants are novel treatments for major depressive disorder (MDD) and work by blocking N-methyl-aspartate receptors (NMDAR), which, in turn, activate the protein synthesis pathway regulated by mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Our recent work demonstrates that the RNA-binding protein Fragile X Mental Retardation Protein (FMRP) is downregulated in dendrites upon treatment with a rapid antidepressant. Here, we show that the behavioral effects of the rapid antidepressant Ro-25-6981 require FMRP expression, and treatment promotes differential mRNA binding to FMRP in an mTORC1-dependent manner. Further, these mRNAs are identified to regulate transsynaptic signaling. Using a novel technique, we show that synapse formation underlying the behavioral effects of Ro-25-6981 requires GABABR-mediated mTORC1 activity in WT animals. Finally, we demonstrate that in an animal model that lacks FMRP expression and has clinical relevance for Fragile X Syndrome (FXS), GABABR activity is detrimental to the effects of Ro-25-6981. These effects are rescued with the combined therapy of blocking GABABRs and NMDARs, indicating that rapid antidepressants alone may not be an effective treatment for people with comorbid FXS and MDD.

molecular biology↗

bioRxiv2019

Chemogenetic inhibition of a monosynaptic projection from the basolateral amygdala to the ventral hippocampus reduces appetitive and consummatory alcohol drinking behaviors

Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co-occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key brain region that is known to contribute to the etiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from this brain region that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety- and fear-related behaviors. However, it is not known if this pathway influences alcohol drinking-related behaviors. Here, we employed a rodent operant drinking regimen that procedurally separates appetitive (e.g. seeking) and consummatory (e.g. intake) behaviors, chemogenetics, and brain region-specific microinjections, to determine if BLA-vHC circuitry influences alcohol drinking-related measures. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety-like behaviors on the elevated plus-maze. We then demonstrated that inhibiting the BLA-vHC pathway significantly reduced appetitive alcohol drinking-related behaviors while having no effect on consummatory measures. Sucrose seeking measures were also reduced following chemogenetic inhibition of this circuit. Taken together, these findings provide the first indication that the BLA-vHC circuit may regulate appetitive alcohol drinking-related behaviors and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor-related disorders. HIGHLIGHTSO_LIThe basolateral amygdala sends a monosynaptic glutamatergic projection to the ventral hippocampus C_LIO_LIInhibiting this circuit reduces anxiety-like behaviors in male Long Evans rats C_LIO_LIInhibition of this pathway also decreases operant alcohol seeking-related behaviors C_LI

neuroscience↗

bioRxiv2018

Chronic intermittent ethanol exposure selectively increases synaptic excitability in the ventral domain of the rat hippocampus

Many studies have implicated hippocampal dysregulation in the pathophysiology of alcohol use disorder (AUD). However, over the past twenty years, a growing body of evidence has revealed distinct functional roles of the dorsal (dHC) and ventral (vHC) hippocampal subregions, with the dHC being primarily involved in spatial learning and memory and the vHC regulating anxiety-and depressive-like behaviors. Notably, to our knowledge, no rodent studies have examined the effects of chronic ethanol exposure on synaptic transmission along the dorsal/ventral axis. To that end, we examined the effects of the chronic intermittent ethanol vapor exposure (CIE) model of AUD on dHC and vHC synaptic excitability. Adult male Long-Evans rats were exposed to CIE or air for 10 days (12 hrs/day; targeting blood ethanol levels of 175-225 mg%) and recordings were made 24 hours into withdrawal. As expected, this protocol increased anxiety-like behaviors on the elevated plus-maze. Extracellular recordings revealed marked CIE-associated increases in synaptic excitation in the CA1 region that were exclusively restricted to the ventral domain of the hippocampus. Western blot analysis of synaptoneurosomal fractions revealed that the expression of two proteins that regulate synaptic strength, GluA2 and SK2, was dysregulated in the vHC, but not the dHC, following CIE. Together, these findings suggest that the ventral CA1 region may be particularly sensitive to the maladaptive effects of chronic ethanol exposure and provide new insight into some of the neural substrates that may contribute to the negative affective state that develops during withdrawal.\n\nHighlightsChronic intermittent ethanol exposure produces robust increases in anxiety-like behavior in male Long Evans rats.\nChronic intermittent ethanol exposure increases synaptic excitability in the ventral, but not the dorsal, domain of the hippocampus.\nThese changes in excitability are associated with alterations in synaptoneurosomal expression of small conductance calcium-activated potassium channels and the GluA2 AMPA receptor subunit that are also restricted to the ventral hippocampus.

neuroscience↗