About

Kevin Wickman, PhD, is a Frederick and Alice Stark Endowed Chair, a Full Professor, and the Head of the Department of Pharmacology at the University of Minnesota. He received his BA in Chemistry (summa cum laude) from Saint Olaf College in Northfield, MN, and earned his PhD in Molecular Neuroscience from the Mayo Foundation for Biomedical Research in Rochester, MN, under the advisement of Dr. David Clapham. Following postdoctoral training at Mayo Clinic Scottsdale with Dr. Sandra Gendler and at Children's Hospital/Harvard Medical School in Boston, MA with Dr. David Clapham, he joined the University of Minnesota as an Assistant Professor in Pharmacology in 1999. He was promoted to Associate Professor in 2005 and to Professor in 2011. Currently, he holds the titles of Distinguished University Teaching Professor and Distinguished McKnight University Professor. His research focuses on mechanisms controlling the excitability of cells in the heart and brain, with the aim of understanding molecular mechanisms that regulate cell excitability to develop safer and more effective treatments for conditions such as cardiac arrhythmias, epilepsy, anxiety, depression, schizophrenia, Down Syndrome, addiction, and pain. His lab employs approaches in electrophysiology, neuromodulation, genetic manipulation, intracranial pharmacology, cardiac physiology, and behavioral assessments to investigate inhibitory signaling pathways and their physiological and pathophysiological relevance.

Research topics

• Biology
• Neuroscience
• Medicine
• Internal medicine
• Cell biology
• Pharmacology
• Chemistry
• Psychology
• Developmental psychology
• Biophysics
• Physics
• Genetics

Selected publications

• AAV-only targeting of ventral tegmental area dopamine neurons for optical self-stimulation studies in mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-12

  articleOpen accessSenior authorCorresponding

  Studies employing optogenetic approaches in rodent models have highlighted the important contribution of ventral tegmental area (VTA) dopamine (DA) neurons to reward, learning, and motivation. Selective manipulation of VTA DA neurons is generally achieved in these studies using transgenic mouse or rat lines that express Cre recombinase under the control of a promoter active in DA neurons, combined with intra-VTA infusion of adeno-associated virus (AAV) vectors harboring Cre recombinase-dependent expression cassettes. Reliance on transgenic Cre driver lines is expensive and decreases study efficiency, and available driver lines have unique limitations. Here, we report the development of an AAV-only approach that permits genetic access to VTA DA neurons and can support optogenetic self-stimulation in mice. We used a 2.5 kb fragment of the mouse tyrosine hydroxylase promoter (mTH) to drive Cre expression in VTA DA neurons. Intra-VTA co-infusion of AAV8-mTH-Cre with an AAV vector harboring a Cre-dependent yellow fluorescent protein expression cassette yielded high efficiency (82%) and high fidelity (73%) targeting of tyrosine hydroxylase-positive VTA neurons in C57BL/6J mice. Co-infusion of AAV8-mTH-Cre with a vector harboring a Cre-dependent channelrhodopsin (ChR2) expression cassette permitted optical regulation of VTA neurons with electrophysiological features consistent with VTA DA neurons. Moreover, C57BL/6J mice expressing ChR2 in VTA DA neurons rapidly acquired optical self-stimulation behavior. Thus, this AAV-only approach should facilitate investigation of VTA DA neuron contributions to reward-related behaviors and permit comparative assessments in reward circuit function in inbred and mutant mouse strains.

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• Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice

  Biology of Sex Differences · 2025-11-06

  articleOpen accessSenior author

  Abstract Background Amyloid β oligomers (oAβ) are a key pathogenic driver in Alzheimer’s Disease (AD). Neuronal G protein-gated inwardly rectifying K + (GIRK/Kir3) channels are important regulators of neuronal excitability and prominent somatodendritic effectors for inhibitory G protein-coupled receptors, including the γ-aminobutyric acid type B receptor (GABA B R). We previously reported a male-specific suppression of GIRK channel activity in hippocampal (HPC) neurons evoked by oAβ in in vitro, ex vivo, and in vivo mouse models of AD, and showed that this adaptation correlated with synaptic and cognitive impairment. Using pharmacological approaches, we showed that this adaptation is mediated by co-activation of cellular prion protein (PrP C ) and metabotropic glutamate receptor 5 (mGluR5) and requires activation of cytosolic phospholipase A2 α (cPLA 2 α). However, the mechanisms underlying the sex specificity was unknown. Given the clinical context that females exhibit a 2-fold higher incidence of AD than males, and the loss of neuroprotective estrogen by menopause contributes to the sex differences in AD, we postulated that estrogen-associated resilience underlies this sex dimorphism of oAβ action. Methods To examine the strength of GIRK-dependent signaling in HPC neurons, we performed electrophysiology in primary HPC cultures from neonatal male and female mice and then measured whole-cell currents evoked by the direct-acting GIRK channel agonist ML297 and the GABA B R-selective agonist baclofen. We used an array of genetic and pharmacological approaches to investigate the molecular mechanism(s) underlying the vulnerability and resilience of GIRK channel activity to oAβ in male and female HPC neurons, respectively. Results We found that resilience to the oAβ-induced and PrP C /mGluR5-dependent suppression of GIRK channel activity in female HPC neurons is conferred by membrane-associated estrogen receptor α (mERα) and caveolin 1 (Cav1). When this resilience factor is blocked or absent, oAβ suppresses GIRK channel activity in female HPC neurons via the same PrP C -mGluR5-cPLA 2 α signaling pathway identified previously in male neurons. Conclusion As estrogen levels decline with aging and menopause, the protective influence of mERα/Cav1 may diminish, unmasking the oAβ-induced suppression of GIRK channel activity and exacerbating disease progression in females. Plain english summary While amyloid β plaques (Aβ) are notable hallmarks of Alzheimer’s Disease (AD), cognitive impairment in the early stages of the disease tracks more closely with the level of soluble Aβ oligomers (oAβ) in the brain. oAβ promotes cognitive deficits by disrupting the balance of excitatory and inhibitory influences on neurons in brain regions important for learning and memory such as the hippocampus, but the underlying molecular targets of oAβ and its pathogenic mechanisms are not fully understood. We recently demonstrated that oAβ weakens the activity of a prominent inhibitory influence on neuronal excitability (the GIRK channel) in the hippocampus of male but not female mice. This sexually dimorphic effect of oAβ was interesting and unexpected given that women are twice as likely to develop AD than men, and because disease progression is more aggressive in women. In this study, we investigated the mechanisms underlying the resilience of GIRK channels in female hippocampal neurons to oAβ. We found that resilience is conferred by estrogen and one of its receptors. When the influence of this receptor is diminished using pharmacological or genetic interventions, oAβ weakens GIRK channel activity in female and male neurons to a similar degree, and via the same mechanism. We speculate that with the onset of menopause, the protective influence of estrogen on GIRK channel activity in the hippocampus begins to wane. This, combined with other female-specific effects of oAβ on neuronal activity, contributes to the increased incidence and severity of AD in females.

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• GABAB receptor-Dependent Regulation of cAMP Dynamics in Hippocampal Neurons (Abstract ID: 166564)

  Journal of Pharmacology and Experimental Therapeutics · 2025-03-01

  articleSenior author
  PublisherDOI

• Global but not myeloid lineage-directed Girk3 deletion increases bone mass in female mice

  JBMR Plus · 2025-08-12

  articleOpen access

  Abstract Germline and osteoblast-directed deletion of G protein-gated inwardly rectifying K+ channel 3 (Girk3) was recently shown to increase bone mass after 18 wk of age in male mice. Here, we show that germline Girk3 deletion also increases trabecular and cortical bone mass and increases the mechanical strength of the femur in female mice after 18 wk of age. Unlike male mice, however, osteoblast-directed Girk3 deletion using 2.3 kb-Col1a1-Cre does not increase bone mass in adult female mice. To discover mechanisms underlying high bone mass in female Girk3−/− mice, bulk RNA-sequencing was performed on 2-d-old calvarial bone, revealing lower expression of proinflammatory cytokines such as IL-1β and IL-6 in Girk3−/− mice. Accordingly, cytokines and chemokines are largely suppressed in the circulation of adult Girk3−/− mice compared to WT littermates. The cytokines GM-CSF, IL-1β, IL-2, and IL-9 are reduced in the serum of both male and female Girk3−/− mice, while eotaxin, IFNγ, MIP-1α, and others are sexually dimorphic. Histomorphometry reveals that osteoclast activity is modestly reduced in Girk3−/− bone, which is supported by in vitro osteoclast resorption assays. However, deletion of Girk3 in myeloid-lineage cells with LysM-Cre is not sufficient to recapitulate high bone mass in either male or female mice. Moreover, female Girk3−/− mice are not protected from ovariectomy-induced bone loss. Finally, single-cell screening using cytometry by time-of-flight in the BM revealed no differences in immune cell abundances due to global Girk3 deletion. Taken together, while Girk3 regulates inflammatory cytokine expression in the bone and serum, deletion of Girk3 in myeloid-lineage cells does not affect bone mass.

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• Chronic ethanol exposure in mice evokes pre‐ and postsynaptic deficits in GABAergic transmission in ventral tegmental area GABA neurons

  British Journal of Pharmacology · 2024-10-02 · 6 citations

  articleOpen accessSenior authorCorresponding

  Abstract Background and purpose GABAergic neurons in mouse ventral tegmental area (VTA) exhibit elevated activity during withdrawal following chronic ethanol exposure. While increased glutamatergic input and decreased GABA A receptor sensitivity have been implicated, the impact of inhibitory signaling in VTA GABA neurons has not been fully addressed. Experimental approach We used electrophysiological and ultrastructural approaches to assess the impact of chronic intermittent ethanol vapour exposure in mice on GABAergic transmission in VTA GABA neurons during withdrawal. We used CRISPR/Cas9 ablation to mimic a somatodendritic adaptation involving the GABA B receptor (GABA B R) in ethanol‐naïve mice to investigate its impact on anxiety‐related behaviour. Key results The frequency of spontaneous inhibitory postsynaptic currents was reduced in VTA GABA neurons following chronic ethanol treatment and this was reversed by GABA B R inhibition, suggesting chronic ethanol strengthens the GABA B R‐dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired‐pulse depression of GABA A receptor‐dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol‐treated mice was reversed by GABA B R inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABA B R activation were reduced following ethanol exposure, attributable to the suppression of GIRK (K ir 3) channel activity. Mimicking this adaptation enhanced anxiety‐related behaviour in ethanol‐naïve mice. Conclusions and implications Chronic ethanol weakens the GABAergic regulation of VTA GABA neurons in mice via pre‐ and postsynaptic mechanisms, likely contributing to their elevated activity during withdrawal and expression of anxiety‐related behaviour. As anxiety can promote relapse during abstinence, interventions targeting VTA GABA neuron excitability could represent new therapeutic strategies for treatment of alcohol use disorder.

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• Stress-induced anxiety-related behavior in mice is driven by enhanced excitability of ventral tegmental area GABA neurons

  Frontiers in Behavioral Neuroscience · 2024-07-17 · 16 citations

  articleOpen accessSenior authorCorresponding

  Introduction Stress and trauma are significant risk factors for many neuropsychiatric disorders and diseases, including anxiety disorders. Stress-induced anxiety symptoms have been attributed to enhanced excitability in circuits controlling fear, anxiety, and aversion. A growing body of evidence has implicated GABAergic neurons of the ventral tegmental area (VTA) in aversion processing and affective behavior. Methods We used an unpredictable footshock (uFS) model, together with electrophysiological and behavioral approaches, to investigate the role of VTA GABA neurons in anxiety-related behavior in mice. Results One day after a single uFS session, C57BL/6J mice exhibited elevated anxiety-related behavior and VTA GABA neuron excitability. The enhanced excitability of VTA GABA neurons was correlated with increased glutamatergic input and a reduction in postsynaptic signaling mediated via GABA A and GABA B receptors. Chemogenetic activation of VTA GABA neurons was sufficient to increase anxiety-related behavior in stress-naïve mice. In addition, chemogenetic inhibition of VTA GABA neurons suppressed anxiety-related behavior in mice exposed to uFS. Discussion These data show that VTA GABA neurons are an early substrate for stress-induced anxiety-related behavior in mice and suggest that approaches mitigating enhanced excitability of VTA GABA neurons may hold promise for the treatment of anxiety provoked by stress and trauma.

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• <i>Girk3</i> deletion increases osteoblast maturation and bone mass accrual in adult male mice

  JBMR Plus · 2024-08-04 · 3 citations

  articleOpen access

  Abstract Osteoporosis and other metabolic bone diseases are prevalent in the aging population. While bone has the capacity to regenerate throughout life, bone formation rates decline with age and contribute to reduced bone density and strength. Identifying mechanisms and pathways that increase bone accrual in adults could prevent fractures and accelerate healing. G protein-gated inwardly rectifying K+ (GIRK) channels are key effectors of G protein-coupled receptor signaling. Girk3 was recently shown to regulate endochondral ossification. Here, we demonstrate that deletion of Girk3 increases bone mass after 18 weeks of age. Male 24-week-old Girk3-/- mice have greater trabecular bone mineral density and bone volume fraction than wildtype (WT) mice. Osteoblast activity is moderately increased in 24-week-old Girk3-/- mice compared to WT mice. In vitro, Girk3-/- bone marrow stromal cells (BMSCs) are more proliferative than WT BMSCs. Calvarial osteoblasts and BMSCs from Girk3-/- mice are also more osteogenic than WT cells, with altered expression of genes that regulate the wingless-related integration site (Wnt) family. Wnt inhibition via Dickkopf-1 (Dkk1) or β-catenin inhibition via XAV939 prevents enhanced mineralization, but not proliferation, in Girk3-/- BMSCs and slows these processes in WT cells. Finally, selective ablation of Girk3 from cells expressing Cre recombinase from the 2.3 kb-Col1a1 promoter, including osteoblasts and osteocytes, is sufficient to increase bone mass and bone strength in male mice at 24 weeks of age. Taken together, these data demonstrate that Girk3 regulates progenitor cell proliferation, osteoblast differentiation, and bone mass accrual in adult male mice.

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• Amyloid-β oligomers trigger sex-dependent inhibition of GIRK channel activity in hippocampal neurons in mice

  Science Signaling · 2024-10-01 · 11 citations

  articleOpen accessSenior authorCorresponding

  Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and cognitive decline, the latter of which is thought to be driven by soluble oligomeric amyloid-β (oAβ). The dysregulation of G protein–gated inwardly rectifying K + (GIRK; also known as Kir3) channels has been implicated in rodent models of AD. Here, seeking mechanistic insights, we uncovered a sex-dependent facet of GIRK-dependent signaling in AD-related amyloid pathophysiology. Synthetic oAβ 1–42 suppressed GIRK-dependent signaling in hippocampal neurons from male mice, but not from female mice. This effect required cellular prion protein, the receptor mGluR5, and production of arachidonic acid by the phospholipase PLA 2 . Although oAβ suppressed GIRK channel activity only in male hippocampal neurons, intrahippocampal infusion of oAβ or genetic suppression of GIRK channel activity in hippocampal pyramidal neurons impaired performance on a memory test in both male and female mice. Moreover, genetic enhancement of GIRK channel activity in hippocampal pyramidal neurons blocked oAβ-induced cognitive impairment in both male and female mice. In APP/PS1 AD model mice, GIRK-dependent signaling was diminished in hippocampal CA1 pyramidal neurons from only male mice before cognitive deficit was detected. However, enhancing GIRK channel activity rescued cognitive deficits in older APP/PS1 mice of both sexes. Thus, whereas diminished GIRK channel activity contributes to cognitive deficits in male mice with increased oAβ burden, enhancing its activity may have therapeutic potential for both sexes.

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• Receptor-dependent influence of R7 RGS proteins on neuronal GIRK channel signaling dynamics

  Progress in Neurobiology · 2024-11-13 · 6 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Domain-selective and sex-dependent regulation of learning and memory in mice by GIRK channel activity in CA1 pyramidal neurons of the dorsal hippocampus

  Learning & Memory · 2024-09-01 · 4 citations

  articleOpen accessSenior author

  (GIRK) channels mediate the postsynaptic inhibitory effect of many neurotransmitters in the hippocampus and are implicated in neurological disorders characterized by cognitive deficits. Here, we show that enhancement or suppression of GIRK channel activity in dorsal CA1 pyramidal neurons disrupted novel object recognition in mice, without impacting open field activity or avoidance behavior. Contextual fear learning was also unaffected, but extinction of contextual fear was disrupted by suppression of GIRK channel activity in male mice. Thus, the strength of GIRK channel activity in dorsal CA1 pyramidal neurons regulates select cognitive task performance in mice.

  PublisherOA PDFDOI

Recent grants

• Architecture of inhibitory G protein signaling in the hippocampus

  NIH · $2.6M · 2023–2028

• The role of RGS proteins in the parasympathetic control of heart rate

  NIH · $3.2M · 2011–2020

• NIH Grant P50DA011806

  NIH · $32.0M · 2014

• Development of an In Vivo, Brain-penetrant GIRK1/2 Potassium Channel Activator

  NIH · $1.6M · 2015–2019

• Alcohol-related suppression of GIRK channel activity in the basal amygdala: a link to plasticity of glutamatergic neurotransmission and withdrawal-associated behavior?

  NIH · $1.7M · 2020–2025

Frequent coauthors

• Ezequiel Marrón Fernández de Velasco

  University of Minnesota

  51 shared

• David E. Clapham

  Howard Hughes Medical Institute

  47 shared

• Nicole C. Victoria

  University of Minnesota

  29 shared

• Allison Anderson

  University of Minnesota

  26 shared

• Hattie Liu

  University of Toronto

  25 shared

• John J. Greer

  University of Alberta

  25 shared

• Richard L. Horner

  University of Toronto

  25 shared

• Jun Ren

  25 shared

Education

• postdoctoral fellow, Cardiology

  Children's Hospital Boston

  1998

• postdoctoral fellow

  Mayo Clinic Arizona

  1997

• PhD, Molecular Neuroscience

  Mayo Clinic Minnesota

  1995

• BA, Chemistry

  Saint Olaf College

  1991

Awards & honors

• Frederick and Alice Stark Endowed Chair
• Distinguished University Teaching Professor
• Distinguished McKnight University Professor