I am a T32 research fellow and research track resident in the Stanford Adult Psychiatry Residency program. I completed my MD-PhD at Baylor College of Medicine, studying learning-associated synaptic plasticity in a model of syndromic autism with in vivo 2-photon imaging. I completed a post-doctoral fellowship at Harvard Medical School, Brigham and Women's Hospital, studying changes in neuronal population activity in syndromic autism with 2-photon genetically encoded calcium indicator imaging.
I am currently developing methods to study the regulation of synaptic plasticity by affective state and mindful presence, using neuronavigated transcranial magnetic stimulation, transcranial ultrasound stimulation, and EEG steady-state visual-evoked potentials. I work closely with the labs of Anthony Norcia, Kim Butts Pauly, and Nolan Williams. My clinical interests include integrated psychodynamic- and mindfulness-based approaches, psychedelic-assisted psychotherapy, and neuromodulation-assisted psychotherapy.

Clinical Focus

  • Residency

All Publications

  • Inhibition of Elevated Ras-MAPK Signaling Normalizes Enhanced Motor Learning and Excessive Clustered Dendritic Spine Stabilization in the MECP2-Duplication Syndrome Mouse Model of Autism. eNeuro Ash, R. T., Buffington, S. A., Park, J., Suter, B., Costa-Mattioli, M., Zoghbi, H. Y., Smirnakis, S. M. 2021


    The inflexible repetitive behaviors and "insistence on sameness" seen in autism imply a defect in neural processes controlling the balance between stability and plasticity of synaptic connections in the brain. It has been proposed that abnormalities in the Ras-ERK/MAPK pathway, a key plasticity-related cell signaling pathway known to drive consolidation of clustered synaptic connections, underlie altered learning phenotypes in autism. However, a link between altered Ras-ERK signaling and clustered dendritic spine plasticity has yet to be explored in an autism animal model in vivo The formation and stabilization of dendritic spine clusters is abnormally increased in the MECP2-duplication syndrome mouse model of syndromic autism, suggesting that ERK signaling may be increased. Here, we show that the Ras-ERK pathway is indeed hyperactive following motor training in MECP2-duplication mouse motor cortex. Pharmacological inhibition of ERK signaling normalizes the excessive clustered spine stabilization and enhanced motor learning behavior in MECP2-duplication mice. We conclude that hyperactive ERK signaling may contribute to abnormal clustered dendritic spine consolidation and motor learning in this model of syndromic autism.Significance StatementIt has been proposed that autism-associated genetic mutations lead to altered learning phenotypes by perturbing cell signaling pathways that regulate synaptic plasticity in the brain. The Ras-ERK/MAPK signaling pathway, which promotes stabilization of dendritic spine clusters, has been particularly implicated in autism spectrum disorder (ASD). Here, we show that Ras-ERK signaling is increased in motor cortex following rotarod training in the MECP2-duplication syndrome mouse model of autism, and that the abnormal motor learning and excessive stabilization of clustered dendritic spines previously observed in MECP2-duplication mice can be rescued by pharmacological inhibition of Ras-ERK signaling. This provides additional support to hypotheses that autistic phenotypes arise from disrupted Ras-ERK signaling and synaptic plasticity and suggest potential future paths for therapeutic intervention.

    View details for DOI 10.1523/ENEURO.0056-21.2021

    View details for PubMedID 34021030

  • Excessive formation and stabilization of dendritic spine clusters in the MECP2 duplication syndrome mouse model of autism. eNeuro Ash, R. T., Park, J., Suter, B., Zoghbi, H. Y., Smirnakis, S. M. 2020


    Autism-associated genetic mutations may perturb the balance between stability and plasticity of synaptic connections in the brain. Here we report an increase in the formation and stabilization of dendritic spines in the cerebral cortex of the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. Increased stabilization is mediated entirely by spines that form cooperatively in 10-micron clusters and is observable across multiple cortical areas both spontaneously and following motor training. Excessive stability of dendritic spine clusters could contribute to behavioral rigidity and other phenotypes in syndromic autism.Significance Statement The inflexible repetitive behaviors, "insistence on sameness," and at times exceptional learning abilities seen in autism imply a defect in the neural processes underlying learning and memory, potentially affecting the balance between stability and plasticity of synaptic connections in the brain. Here we report a pathological bias toward stability of newly formed dendritic spines in the MECP2-duplication mouse model of autism. Enhanced spine stability is mediated entirely by spines aggregating within 10 m of each other, in clusters. Enhanced clustered spine stability is observable in multiple brain areas both at rest and during motor training. The results suggest that some phenotypes of autism could arise from abnormal consolidation of clustered synaptic connections.

    View details for DOI 10.1523/ENEURO.0282-20.2020

    View details for PubMedID 33168618

  • Contribution of apical and basal dendrites to orientation encoding in mouse V1 L2/3 pyramidal neurons. Nature communications Park, J., Papoutsi, A., Ash, R. T., Marin, M. A., Poirazi, P., Smirnakis, S. M. 2019; 10 (1): 5372


    Pyramidal neurons integrate synaptic inputs from basal and apical dendrites to generate stimulus-specific responses. It has been proposed that feed-forward inputs to basal dendrites drive a neuron's stimulus preference, while feedback inputs to apical dendrites sharpen selectivity. However, how a neuron's dendritic domains relate to its functional selectivity has not been demonstrated experimentally. We performed 2-photon dendritic micro-dissection on layer-2/3 pyramidal neurons in mouse primary visual cortex. We found that removing the apical dendritic tuft did not alter orientation-tuning. Furthermore, orientation-tuning curves were remarkably robust to the removal of basal dendrites: ablation of 2 basal dendrites was needed to cause a small shift in orientation preference, without significantly altering tuning width. Computational modeling corroborated our results and put limits on how orientation preferences among basal dendrites differ in order to reproduce the post-ablation data. In conclusion, neuronal orientation-tuning appears remarkably robust to loss of dendritic input.

    View details for DOI 10.1038/s41467-019-13029-0

    View details for PubMedID 31772192

  • Increased Axonal Bouton Stability during Learning in the Mouse Model of MECP2 Duplication Syndrome ENEURO Ash, R. T., Fahey, P. G., Park, J., Zoghbi, H. Y., Smirnakis, S. M. 2018; 5 (3)


    MECP2 duplication syndrome is an X-linked form of syndromic autism caused by genomic duplication of the region encoding methyl-CpG-binding protein 2 (MECP2). Mice overexpressing MECP2 demonstrate social impairment, behavioral inflexibility, and altered patterns of learning and memory. Previous work showed abnormally increased stability of dendritic spines formed during motor training in the apical tuft of primary motor cortex (area M1) corticospinal neurons in the MECP2 duplication mouse model. In the current study, we measure the structural plasticity of axonal boutons in layer 5 pyramidal neuron projections to layer 1 of area M1 during motor training. In wild-type littermate control mice, we find that during rotarod training the bouton formation rate changes minimally, if at all, while the bouton elimination rate more than doubles. Notably, the observed upregulation in bouton elimination with training is absent in MECP2 duplication mice. This result provides further evidence of an imbalance between structural stability and plasticity in this form of syndromic autism. Furthermore, the observation that axonal bouton elimination more than doubles with motor training in wild-type animals contrasts with the increase of dendritic spine consolidation observed in corticospinal neurons at the same layer. This dissociation suggests that different area M1 microcircuits may manifest different patterns of structural synaptic plasticity during motor training.

    View details for DOI 10.1523/ENEURO.0056-17.2018

    View details for Web of Science ID 000442165100006

    View details for PubMedID 30105297

    View details for PubMedCentralID PMC6086213

  • Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model. Neuron Lu, H. n., Ash, R. T., He, L. n., Kee, S. E., Wang, W. n., Yu, D. n., Hao, S. n., Meng, X. n., Ure, K. n., Ito-Ishida, A. n., Tang, B. n., Sun, Y. n., Ji, D. n., Tang, J. n., Arenkiel, B. R., Smirnakis, S. M., Zoghbi, H. Y. 2016; 91 (4): 739–47


    Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice.

    View details for DOI 10.1016/j.neuron.2016.07.018

    View details for PubMedID 27499081

    View details for PubMedCentralID PMC5019177

  • Dynamic Control of Excitatory Synapse Development by a Rac1 GEF/GAP Regulatory Complex DEVELOPMENTAL CELL Um, K., Niu, S., Duman, J. G., Cheng, J. X., Tu, Y., Schwechter, B., Liu, F., Hiles, L., Narayanan, A. S., Ash, R. T., Mulherkar, S., Alpadi, K., Smirnakis, S. M., Tolias, K. F. 2014; 29 (6): 701–15


    The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here, we identify a regulatory complex composed of a Rac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development. Disruption of Bcr function within this complex increases Rac1 activity and dendritic spine remodeling, resulting in excessive synaptic growth that is rescued by Tiam1 inhibition. Notably, EphB receptors utilize the Tiam1-Bcr complex to control synaptogenesis. Following EphB activation, Tiam1 induces Rac1-dependent spine formation, whereas Bcr prevents Rac1-mediated receptor internalization, promoting spine growth over retraction. The finding that a Rac-specific GEF/GAP complex is required to maintain optimal levels of Rac1 signaling provides an important insight into the regulation of small GTPases.

    View details for DOI 10.1016/j.devcel.2014.05.011

    View details for Web of Science ID 000338174600008

    View details for PubMedID 24960694

    View details for PubMedCentralID PMC4111230

  • Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo EUROPEAN JOURNAL OF NEUROSCIENCE Kim, J., Ash, R. T., Ceballos-Diaz, C., Levites, Y., Golde, T. E., Smirnakis, S. M., Jankowsky, J. L. 2013; 37 (8): 1203–20


    The neonatal intraventricular injection of adeno-associated virus has been shown to transduce neurons widely throughout the brain, but its full potential for experimental neuroscience has not been adequately explored. We report a detailed analysis of the method's versatility with an emphasis on experimental applications where tools for genetic manipulation are currently lacking. Viral injection into the neonatal mouse brain is fast, easy, and accesses regions of the brain including the cerebellum and brainstem that have been difficult to target with other techniques such as electroporation. We show that viral transduction produces an inherently mosaic expression pattern that can be exploited by varying the titer to transduce isolated neurons or densely-packed populations. We demonstrate that the expression of virally-encoded proteins is active much sooner than previously believed, allowing genetic perturbation during critical periods of neuronal plasticity, but is also long-lasting and stable, allowing chronic studies of aging. We harness these features to visualise and manipulate neurons in the hindbrain that have been recalcitrant to approaches commonly applied in the cortex. We show that viral labeling aids the analysis of postnatal dendritic maturation in cerebellar Purkinje neurons by allowing individual cells to be readily distinguished, and then demonstrate that the same sparse labeling allows live in vivo imaging of mature Purkinje neurons at a resolution sufficient for complete analytical reconstruction. Given the rising availability of viral constructs, packaging services, and genetically modified animals, these techniques should facilitate a wide range of experiments into brain development, function, and degeneration.

    View details for DOI 10.1111/ejn.12126

    View details for Web of Science ID 000317850800001

    View details for PubMedID 23347239

    View details for PubMedCentralID PMC3628093

  • Dendritic arborization and spine dynamics are abnormal in the mouse model of MECP2 duplication syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience Jiang, M. n., Ash, R. T., Baker, S. A., Suter, B. n., Ferguson, A. n., Park, J. n., Rudy, J. n., Torsky, S. P., Chao, H. T., Zoghbi, H. Y., Smirnakis, S. M. 2013; 33 (50): 19518–33


    MECP2 duplication syndrome is a childhood neurological disorder characterized by intellectual disability, autism, motor abnormalities, and epilepsy. The disorder is caused by duplications spanning the gene encoding methyl-CpG-binding protein-2 (MeCP2), a protein involved in the modulation of chromatin and gene expression. MeCP2 is thought to play a role in maintaining the structural integrity of neuronal circuits. Loss of MeCP2 function causes Rett syndrome and results in abnormal dendritic spine morphology and decreased pyramidal dendritic arbor complexity and spine density. The consequences of MeCP2 overexpression on dendritic pathophysiology remain unclear. We used in vivo two-photon microscopy to characterize layer 5 pyramidal neuron spine turnover and dendritic arborization as a function of age in transgenic mice expressing the human MECP2 gene at twice the normal levels of MeCP2 (Tg1; Collins et al., 2004). We found that spine density in terminal dendritic branches is initially higher in young Tg1 mice but falls below control levels after postnatal week 12, approximately correlating with the onset of behavioral symptoms. Spontaneous spine turnover rates remain high in older Tg1 animals compared with controls, reflecting the persistence of an immature state. Both spine gain and loss rates are higher, with a net bias in favor of spine elimination. Apical dendritic arbors in both simple- and complex-tufted layer 5 Tg1 pyramidal neurons have more branches of higher order, indicating that MeCP2 overexpression induces dendritic overgrowth. P70S6K was hyperphosphorylated in Tg1 somatosensory cortex, suggesting that elevated mTOR signaling may underlie the observed increase in spine turnover and dendritic growth.

    View details for DOI 10.1523/JNEUROSCI.1745-13.2013

    View details for PubMedID 24336718

    View details for PubMedCentralID PMC3858623