Konstantin Kaganovsky

All Publications

• Antisense oligonucleotide therapeutic approach for Timothy syndrome. Nature Chen, X., Birey, F., Li, M. Y., Revah, O., Levy, R., Thete, M. V., Reis, N., Kaganovsky, K., Onesto, M., Sakai, N., Hudacova, Z., Hao, J., Meng, X., Nishino, S., Huguenard, J., Pașca, S. P. 2024; 628 (8009): 818-825

  Abstract

  Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

  View details for DOI 10.1038/s41586-024-07310-6

  View details for PubMedID 38658687

  View details for PubMedCentralID 1149428

• Hippocampal place code plasticity in CA1 requires postsynaptic membrane fusion. bioRxiv : the preprint server for biology Plitt, M. H., Kaganovsky, K., Südhof, T. C., Giocomo, L. M. 2023

  Abstract

  Rapid delivery of glutamate receptors to the postsynaptic membrane via vesicle fusion is a central component of synaptic plasticity. However, it is unknown how this process supports specific neural computations during behavior. To bridge this gap, we combined conditional genetic deletion of a component of the postsynaptic membrane fusion machinery, Syntaxin3 (Stx3), in hippocampal CA1 neurons of mice with population in vivo calcium imaging. This approach revealed that Stx3 is necessary for forming the neural dynamics that support novelty processing, spatial reward memory and offline memory consolidation. In contrast, CA1 Stx3 was dispensable for maintaining aspects of the neural code that exist presynaptic to CA1 such as representations of context and space. Thus, manipulating postsynaptic membrane fusion identified computations that specifically require synaptic restructuring via membrane trafficking in CA1 and distinguished them from neural representation that could be inherited from upstream brain regions or learned through other mechanisms.

  View details for DOI 10.1101/2023.11.20.567978

  View details for PubMedID 38045362

  View details for PubMedCentralID PMC10690209

• Motor Impairments and Dopaminergic Defects Caused by Loss of Leucine-Rich Repeat Kinase 2 Function in Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience Huang, G., Bloodgood, D. W., Kang, J., Shahapal, A., Chen, P., Kaganovsky, K., Kim, J., Ding, J., Shen, J. 2022

  Abstract

  Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD), but the pathogenic mechanism underlying LRRK2 mutations remains unresolved. In this study, we investigate the consequence of inactivation of LRRK2 and its functional homolog LRRK1 in male and female mice up to 25months of age using behavioral, neurochemical, neuropathological, and ultrastructural analyses. We report that LRRK1 and LRRK2 double knock-out (LRRK DKO) mice exhibit impaired motor coordination at 12months of age before the onset of DA neuron loss in the substantia nigra (SNpc). Moreover, LRRK DKO mice develop age-dependent, progressive loss of DA terminals in the striatum. Evoked dopamine release measured by fast-scan cyclic voltammetry in the dorsal striatum is also reduced in the absence of LRRK. Furthermore, LRRK DKO mice at 20-25months of age show substantial loss of DA neurons in the SNpc. The surviving SNpc neurons in LRRK DKO mice at 25months of age accumulate large numbers of autophagic and autolysosomal vacuoles and are accompanied with microgliosis. Surprisingly, the cerebral cortex is unaffected, as shown by normal cortical volume and neuron number as well as unchanged number of apoptotic cells and microglia in LRRK DKO mice at 25months. These findings show that loss of LRRK function causes impairments in motor coordination, degeneration of DA terminals, reduction of evoked DA release, and selective loss of DA neurons in the SNpc, indicating that LRRK DKO mice are unique models for better understanding DA neurodegeneration in PD.SIGNIFICANCE STATEMENTOur current study employs a genetic approach to uncover the normal function of the LRRK family in the brain during mouse life span. Our multidisciplinary analysis demonstrates a critical normal physiological role of LRRK in maintaining the integrity and function of dopaminergic terminals and neurons in the aging brain, and show that LRRK DKO mice recapitulate several key features of PD and provide unique mouse models for elucidating molecular mechanisms underlying dopaminergic neurodegeneration in PD.

  View details for DOI 10.1523/JNEUROSCI.0140-22.2022

  View details for PubMedID 35534227

• Functional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum. Nature communications Puighermanal, E. n., Castell, L. n., Esteve-Codina, A. n., Melser, S. n., Kaganovsky, K. n., Zussy, C. n., Boubaker-Vitre, J. n., Gut, M. n., Rialle, S. n., Kellendonk, C. n., Sanz, E. n., Quintana, A. n., Marsicano, G. n., Martin, M. n., Rubinstein, M. n., Girault, J. A., Ding, J. B., Valjent, E. n. 2020; 11 (1): 1957

  Abstract

  Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.

  View details for DOI 10.1038/s41467-020-15716-9

  View details for PubMedID 32327644

• Punishment of alcohol-reinforced responding in alcohol preferring P rats reveals a bimodal population: Implications for models of compulsive drug seeking PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Marchant, N. J., Campbell, E. J., Kaganovsky, K. 2018; 87: 68–77

  Abstract

  Individual variations in animal behaviour can be used to describe relationships between different constructs, as well as the underlying neurobiological mechanisms responsible for such variation. In humans, variation in the expression of certain traits contributes to the onset of psychopathologies, such as drug addiction. Addiction is characterised by persistent drug use despite negative consequences, but it occurs in only a sub-population of drug users. Compulsive drug use is modelled in laboratory animals by punishing a drug-reinforced operant response. It has been reported that there is individual variability in the response to punishment, and in this report we aim to further define the conditions under which this variation can be observed. We have previously used footshock punishment to suppress alcohol seeking in an animal model of context-induced relapse to alcohol seeking after punishment-imposed abstinence. Here we present a re-examination of the training and punishment data from a large cohort of rats (n=499) collected over several years. We found evidence for a bimodal distribution in the response to punishment in alcohol preferring P rats. We only observed this population split when rats received constant shock intensity for three sessions, but not when increasing shock intensity was used. This observation provides evidence for the existence of two distinct groups of rats, defined by their response to punishment, in an otherwise homogeneous population. The implications of this observation are discussed in reference to prior observations using punishment of other addictive drugs (cocaine and methamphetamine), the potential causes of this phenomenon, and with broader implications for the cause of alcohol and drug addiction in humans.

  View details for DOI 10.1016/j.pnpbp.2017.07.020

  View details for Web of Science ID 000441507700008

  View details for PubMedID 28754407

  View details for PubMedCentralID PMC5785579

• The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival CELL Maeder, C. I., Kim, J., Liang, X., Kaganovsky, K., Shen, A., Li, Q., Li, Z., Wang, S., Xu, X., Li, J., Xiang, Y., Ding, J. B., Shen, K. 2018; 174 (6): 1436-+

  View details for DOI 10.1016/j.cell.2018.07.046

  View details for Web of Science ID 000443841000013

• The THO Complex Coordinates Transcripts for Synapse Development and Dopamine Neuron Survival. Cell Maeder, C. I., Kim, J., Liang, X., Kaganovsky, K., Shen, A., Li, Q., Li, Z., Wang, S., Xu, X. Z., Li, J. B., Xiang, Y. K., Ding, J. B., Shen, K. 2018

  Abstract

  Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export complex (THOC) as an important regulator of presynapse development in C.elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are retained in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses, and compromised dopamine function. CRE binding protein (CREB) interacts with THOC to mark synaptic transcripts for efficient nuclear export. Deletion of Thoc5, a THOC subunit, in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the substantia nigra compacta. These cellular defects lead to abrogated dopamine release, ataxia, and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for neuronal differentiation and survival.

  View details for PubMedID 30146163

• Cue-induced food seeking after punishment is associated with increased Fos expression in the lateral hypothalamus and basolateral and medial amygdala. Behavioral neuroscience Campbell, E. J., Barker, D. J., Nasser, H. M., Kaganovsky, K., Dayas, C. V., Marchant, N. J. 2017; 131 (2): 155-67

  Abstract

  In humans, relapse to unhealthy eating habits following dieting is a significant impediment to obesity treatment. Food-associated cues are one of the main triggers of relapse to unhealthy eating during self-imposed abstinence. Here we report a behavioral method examining cue-induced relapse to food seeking following punishment-induced suppression of food taking. We trained male rats to lever press for food pellets that were delivered after a 10-s conditional stimulus (CS) (appetitive). Following training, 25% of reinforced lever presses resulted in the presentation of a compound stimulus consisting of a novel CS (aversive) and the appetitive CS followed by a pellet and footshock. After punishment-imposed abstinence, we tested the rats in an extinction test where lever pressing resulted in the presentation of either the appetitive or aversive CS. We then compared activity of lateral hypothalamus (LH) and associated extrahypothalamic regions following this test. We also assessed Fos expression in LH orexin and GABA neurons. We found that cue-induced relapse of food seeking on test was higher in rats tested with the appetitive CS compared to the aversive CS. Relapse induced by the appetitive CS was associated with increased Fos expression in LH, caudal basolateral amygdala (BLA), and medial amygdala (MeA). This relapse was also associated with increased Fos expression in LH orexin and VGAT-expressing neurons. These data show that relapse to food seeking can be induced by food-associated cues after punishment-imposed abstinence, and this relapse is associated with increased activity in LH, caudal BLA, and MeA. (PsycINFO Database Record

  View details for DOI 10.1037/bne0000185

  View details for PubMedID 28221079

• The Locomotion Tug-of-War: Cholinergic and Dopaminergic Interactions Outside the Striatum. Neuron Kaganovsky, K. n., Ding, J. B. 2017; 96 (6): 1208–10

  Abstract

  In this issue of Neuron, Moehle et al. (2017) demonstrate that presynaptic muscarinic receptors counteract the effects of dopamine in an output nucleus of the basal ganglia. They provide intracellular, anatomical, and network-level mechanisms for this cholinergic-dopaminergic interplay.

  View details for PubMedID 29268090

• How Do Microtubule Dynamics Relate to the Hallmarks of Learning and Memory? JOURNAL OF NEUROSCIENCE Kaganovsky, K., Wang, C. 2016; 36 (22): 5911–13

  View details for PubMedID 27251613

• Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence. The Journal of neuroscience : the official journal of the Society for Neuroscience Marchant, N. J., Campbell, E. J., Whitaker, L. R., Harvey, B. K., Kaganovsky, K., Adhikary, S., Hope, B. T., Heins, R. C., Prisinzano, T. E., Vardy, E., Bonci, A., Bossert, J. M., Shaham, Y. 2016; 36 (11): 3281-94

  Abstract

  In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse.In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence.

  View details for DOI 10.1523/JNEUROSCI.4299-15.2016

  View details for PubMedID 26985037

  View details for PubMedCentralID PMC4792939

• A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence. Behavioral neuroscience Marchant, N. J., Kaganovsky, K. 2015; 129 (3): 281-91

  Abstract

  In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here, we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol-preferring "P rats" to self-administer 20% alcohol in Context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in Context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment.

  View details for DOI 10.1037/bne0000050

  View details for PubMedID 25914922

  View details for PubMedCentralID PMC4451375

• A critical role of lateral hypothalamus in context-induced relapse to alcohol seeking after punishment-imposed abstinence. The Journal of neuroscience : the official journal of the Society for Neuroscience Marchant, N. J., Rabei, R., Kaganovsky, K., Caprioli, D., Bossert, J. M., Bonci, A., Shaham, Y. 2014; 34 (22): 7447-57

  Abstract

  In human alcoholics, abstinence is often self-imposed, despite alcohol availability, because of the negative consequences of excessive use. During abstinence, relapse is often triggered by exposure to contexts associated with alcohol use. We recently developed a rat model that captures some features of this human condition: exposure to the alcohol self-administration environment (context A), after punishment-imposed suppression of alcohol self-administration in a different environment (context B), provoked renewal of alcohol seeking in alcohol-preferring P rats. The mechanisms underlying context-induced renewal of alcohol seeking after punishment-imposed abstinence are unknown. Here, we studied the role of the lateral hypothalamus (LH) and its forebrain projections in this effect. We first determined the effect of context-induced renewal of alcohol seeking on Fos (a neuronal activity marker) expression in LH. We next determined the effect of LH reversible inactivation by GABAA + GABAB receptor agonists (muscimol + baclofen) on this effect. Finally, we determined neuronal activation in brain areas projecting to LH during context-induced renewal tests by measuring double labeling of the retrograde tracer cholera toxin subunit B (CTb; injected in LH) with Fos. Context-induced renewal of alcohol seeking after punishment-imposed abstinence was associated with increased Fos expression in LH. Additionally, renewal was blocked by muscimol + baclofen injections into LH. Finally, double-labeling analysis of CTb + Fos showed that context-induced renewal of alcohol seeking after punishment-imposed abstinence was associated with selective activation of accumbens shell neurons projecting to LH. The results demonstrate an important role of LH in renewal of alcohol seeking after punishment-imposed abstinence and suggest a role of accumbens shell projections to LH in this form of relapse.

  View details for DOI 10.1523/JNEUROSCI.0256-14.2014

  View details for PubMedID 24872550

  View details for PubMedCentralID PMC4035512