Alarcon, Juan Marcos

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Alarcon, Juan Marcos

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Biography

Our laboratory explores how experiences change brain function in neurotypical laboratory rodents as well as in animal models of brain disease. My background training in electrophysiology started with ion channels biophysics during my PhD under Dr. Eduardo Rojas (Univ. of Chile), and then with hippocampal synaptic plasticity function during my post-doc under Dr. Eric Kandel (Columbia Univ.). At SUNY Downstate Health Sciences University (DHSU), I joined an expert and collegial team of scientists that allowed me to expand our investigational scope to explore neurobiological processes at the gene expression level (e.g. RNAseq), synaptic function level (e.g. synaptic and neuronal electrophysiology), neuronal ensemble organization (e.g. activity-dependent immediate early gene tagging), and behavior (e.g. rodent memory tasks). Our current research projects aim to test the connection between neurodevelopmental mechanisms and brain function in animal models of autism. Inspired by this and concomitant with DHSU mission, I co-developed and co-lead with Dr. Jenny Libien an R25 summer research course for young under-represented minorities to investigate the neurobiology of autism spectrum disorders. Overall, our goal is to provide a deeper insight on the nature and mechanisms of neurodevelopmental disorders.

Publication Search Results

Now showing 1 - 10 of 30

Open Access
Expression of Constitutively Active CREB Protein Facilitates the Late Phase of Long-Term Potentiation by Enhancing Synaptic Capture
(Elsevier BV, 2002-03) Barco, Angel; Alarcon, Juan M.; Kandel, Eric R.
Restricted and regulated expression in mice of VP16-CREB, a constitutively active form of CREB, in hippocampal CA1 neurons lowers the threshold for eliciting a persistent late phase of long-term potentiation (L-LTP) in the Schaffer collateral pathway. This L-LTP has unusual properties in that its induction is not dependent on transcription. Pharmacological and two-pathway experiments suggest a model in which VP16-CREB activates the transcription of CRE-driven genes and leads to a cell-wide distribution of proteins that prime the synapses for subsequent synapse-specific capture of L-LTP by a weak stimulus. Our analysis indicates that synaptic capture of CRE-driven gene products may be sufficient for consolidation of LTP and provides insight into the molecular mechanisms of synaptic tagging and synapse-specific potentiation.
Open Access
A Role in Learning for SRF: Deletion in the Adult Forebrain Disrupts LTD and the Formation of an Immediate Memory of a Novel Context
(Elsevier BV, 2006-04) Etkin, Amit; Alarcón, Juan Marcos; Weisberg, Stuart P.; Touzani, Khalid; Huang, Yan You; Nordheim, Alfred; Kandel, Eric R.
Whereas significant insight exists as to how LTP-related changes can contribute to the formation of long-term memory, little is known about the role of hippocampal LTD-like changes in learning and memory storage. We describe a mouse lacking the transcription factor SRF in the adult forebrain. This mouse could not acquire a hippocampus-based immediate memory for a novel context even across a few minute timespan, which led to a profound but selective deficit in explicit spatial memory. These animals were also impaired in the induction of LTD, including LTD triggered by a cholinergic agonist. Moreover, genes regulating two processes essential for LTD-calcium release from intracellular stores and phosphatase activation-were abnormally expressed in knockouts. These findings suggest that for the hippocampus to form associative spatial memories through LTP-like processes, it must first undergo learning of the context per se through exploration and the learning of familiarity, which requires LTD-like processes.
Open Access
Phencyclidine Disrupts Neural Coordination and Cognitive Control by Dysregulating Translation
(Elsevier BV, 2024-01) Park, Eun Hye; Kao, Hsin-Yi; Jourdi, Hussam; van Dijk, Milenna T.; Carrillo-Segura, Simón; Tunnell, Kayla W.; Gutierrez, Jeffrey; Wallace, Emma J.; Troy-Regier, Matthew; Radwan, Basma; Lesburguères, Edith; Alarcon, Juan Marcos; Fenton, André A.
Background: Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive NMDA receptor (NMDAR) antagonist impairs cognition remains unknown. Methods: The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects with the effects of inhibitors of protein synthesis, group I metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. Results: Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity and impaired active place avoidance, despite the rodents having learned the task before PCP administration. Consistent with metabotropic actions, PCP exaggerated protein synthesis-dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression. Pretreatment with anisomycin or the mGluR1/5 antagonist MPEP, both of which repress translation, prevented PCP-induced discoordination and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR antagonist NVP-AAM077 unbalanced translation that engages the Akt, mTOR (mechanistic target of rapamycin), and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. Conclusions: PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, and leading to neural discoordination that is central to the cognitive and sensorimotor impairments.
Open Access
Spatially resolved transcriptomic signatures of hippocampal subregions and Arc-expressing ensembles in active place avoidance memory
(Frontiers Media SA, 2024-10-31) Vingan, Isaac; Phatarpekar, Shwetha; Tung, Victoria Sook Keng; Hernández, Alejandro Iván; Evgrafov, Oleg V.; Alarcon, Juan Marcos
The rodent hippocampus is a spatially organized neuronal network that supports the formation of spatial and episodic memories. We conducted bulk RNA sequencing and spatial transcriptomics experiments to measure gene expression changes in the dorsal hippocampus following the recall of active place avoidance (APA) memory. Through bulk RNA sequencing, we examined the gene expression changes following memory recall across the functionally distinct subregions of the dorsal hippocampus. We found that recall induced differentially expressed genes (DEGs) in the CA1 and CA3 hippocampal subregions were enriched with genes involved in synaptic transmission and synaptic plasticity, while DEGs in the dentate gyrus (DG) were enriched with genes involved in energy balance and ribosomal function. Through spatial transcriptomics, we examined gene expression changes following memory recall across an array of spots encompassing putative memory-associated neuronal ensembles marked by the expression of the IEGs Arc, Egr1, and c-Jun. Within samples from both trained and untrained mice, the subpopulations of spatial transcriptomic spots marked by these IEGs were transcriptomically and spatially distinct from one another. DEGs detected between Arc + and Arc- spots exclusively in the trained mouse were enriched in several memory-related gene ontology terms, including "regulation of synaptic plasticity" and "memory." Our results suggest that APA memory recall is supported by regionalized transcriptomic profiles separating the CA1 and CA3 from the DG, transcriptionally and spatially distinct IEG expressing spatial transcriptomic spots, and biological processes related to synaptic plasticity as a defining the difference between Arc + and Arc- spatial transcriptomic spots.
Open Access
Learning-induced and stathmin-dependent changes in microtubule stability are critical for memory and disrupted in ageing
(Springer Science and Business Media LLC, 2014-07-10) Uchida, Shusaku; Martel, Guillaume; Pavlowsky, Alice; Takizawa, Shuichi; Hevi, Charles; Watanabe, Yoshifumi; Kandel, Eric R.; Alarcon, Juan Marcos; Shumyatsky, Gleb P.
Changes in the stability of microtubules regulate many biological processes, but their role in memory remains unclear. Here we show that learning causes biphasic changes in the microtubule-associated network in the hippocampus. In the early phase, stathmin is dephosphorylated, enhancing its microtubule-destabilizing activity by promoting stathmin-tubulin binding, whereas in the late phase these processes are reversed leading to an increase in microtubule/KIF5-mediated localization of the GluA2 subunit of AMPA receptors at synaptic sites. A microtubule stabilizer paclitaxel decreases or increases memory when applied at the early or late phases, respectively. Stathmin mutations disrupt changes in microtubule stability, GluA2 localization, synaptic plasticity and memory. Aged wild-type mice show impairments in stathmin levels, changes in microtubule stability and GluA2 localization. Blocking GluA2 endocytosis rescues memory deficits in stathmin mutant and aged wild-type mice. These findings demonstrate a role for microtubules in memory in young adult and aged individuals.
Open Access
Synapse-specific stabilization of plasticity processes: The synaptic tagging and capture hypothesis revisited 10 years later
(Elsevier BV, 2008-01) Barco, Angel; Lopez de Armentia, Mikel; Alarcon, Juan M.
A decade ago, the synaptic tagging hypothesis was proposed to explain how newly synthesized plasticity products can be specifically targeted to active synapses. A growing number of studies have validated the seminal findings that gave rise to this model, as well as contributed to unveil and expand the range of mechanisms underlying late-associativity and neuronal computation. Here, we will review what it was learnt during this past decade regarding the cellular and molecular mechanisms underlying synaptic tagging and synaptic capture. The accumulated experimental evidence has widened the theoretical framework set by the synaptic tagging and capture (STC) model and introduced concepts that were originally considered part of alternative models for explaining synapse-specific long-term potentiation (LTP). As a result, we believe that the STC model, now improved and expanded with these new ideas and concepts, still represents the most compelling hypothesis to explain late-associativity in synapse-specific plasticity processes. We will also discuss the impact of this model in our view of the integrative capability of neurons and associative learning.
Open Access
Dopamine release and dopamine-related gene expression in the amygdala are modulated by the gastrin-releasing peptide in opposite directions during stress-enhanced fear learning and extinction
(Springer Science and Business Media LLC, 2024-11-23) Morishita, Yoshikazu; Fuentes, Ileana; Gonzalez-Salinas, Sofia; Favate, John; Mejaes, Jennifer; Zushida, Ko; Nishi, Akinori; Hevi, Charles; Goldsmith, Noriko; Buyske, Steve; Sillivan, Stephanie E.; Miller, Courtney A.; Kandel, Eric R.; Uchida, Shusaku; Shah, Premal; Alarcon, Juan Marcos; Barker, David J.; Shumyatsky, Gleb P.
Fear extinction leads to a decrease of originally acquired fear responses after the threat is no longer present. Fear extinction is adaptive and critical for organism's survival, but deficits in extinction may lead to exaggerated fear in animals or post-traumatic stress disorder (PTSD) in humans. Dopamine has recently emerged as essential for fear extinction and PTSD, however the neural circuits serving this dopamine function are only beginning to be investigated, and the dopamine intracellular signaling pathways are unknown. We generated gastrin-releasing peptide gene knockout (Grp-/-) mice and found that they exhibit enhanced fear memory in a stress-enhanced fear learning (SEFL) paradigm, which combines stress exposure and fear extinction, two features critical for developing PTSD. Using in vivo fiber photometry to record dopamine signals, we found that the susceptibility of Grp-/- mice to SEFL is paralleled by an increase in basolateral amygdala (BLA) dopaminergic binding during fear conditioning and early extinction. Combined optogenetics and ex vivo electrophysiology showed an increase in presynaptic ventral tegmental area (VTA)-BLA connectivity in Grp-/- mice, demonstrating a role of dysregulated input from the VTA on BLA function in the absence of the GRP. When examining gene transcription using RNA-seq and qPCR, we discovered concerted down-regulation in dopamine-related genes in the BLA of Grp-/- mice following long-term SEFL memory recall that was not observed in naïve conditions. These experiments demonstrate that the GRP regulates dopamine function in stress-enhanced fear processing and identify the Grp as the first gene known to regulate dopaminergic control of fear extinction.
Open Access
Interaction between Long-Term Potentiation and Depression in CA1 Synapses: Temporal Constrains, Functional Compartmentalization and Protein Synthesis
(Public Library of Science (PLoS), 2012-01-17) Pavlowsky, Alice; Alarcon, Juan Marcos
Information arriving at a neuron via anatomically defined pathways undergoes spatial and temporal encoding. A proposed mechanism by which temporally and spatially segregated information is encoded at the cellular level is based on the interactive properties of synapses located within and across functional dendritic compartments. We examined cooperative and interfering interactions between long-term synaptic potentiation (LTP) and depression (LTD), two forms of synaptic plasticity thought to be key in the encoding of information in the brain. Two approaches were used in CA1 pyramidal neurons of the mouse hippocampus: (1) induction of LTP and LTD in two separate synaptic pathways within the same apical dendritic compartment and across the basal and apical dendritic compartments; (2) induction of LTP and LTD separated by various time intervals (0-90 min). Expression of LTP/LTD interactions was spatially and temporally regulated. While they were largely restricted within the same dendritic compartment (compartmentalized), the nature of the interaction (cooperation or interference) depended on the time interval between inductions. New protein synthesis was found to regulate the expression of the LTP/LTD interference. We speculate that mechanisms for compartmentalization and protein synthesis confer the spatial and temporal modulation by which neurons encode multiplex information in plastic synapses.
Open Access
cAMP Response Element-Binding Protein-Mediated Gene Expression Increases the Intrinsic Excitability of CA1 Pyramidal Neurons
(Society for Neuroscience, 2007-12-12) Lopez de Armentia, Mikel; Jancic, Dragana; Olivares, Roman; Alarcon, Juan M.; Kandel, Eric R.; Barco, Angel
To investigate the role of CREB-mediated gene expression on the excitability of CA1 pyramidal neurons, we obtained intracellular recordings from pyramidal neurons of transgenic mice expressing a constitutively active form of CREB, VP16-CREB, in a regulated and restricted manner. We found that transgene expression increased the neuronal excitability and inhibited the slow and medium afterhyperpolarization currents. These changes may contribute to the reduced threshold for LTP observed in these mice. When strong transgene expression was turned on for prolonged period of time, these mice also showed a significant loss of hippocampal neurons and sporadic epileptic seizures. These deleterious effects were dose dependent and could be halted, but not reversed by turning off transgene expression. Our experiments reveal a new role for hippocampal CREB-mediated gene expression, identify the slow afterhyperpolarization as a primary target of CREB action, provide a new mouse model to investigate temporal lobe epilepsy and associated neurodegeneration, and illustrate the risks of cell death associated to a sustained manipulation of this pathway. As a result, our study has important implications for both the understanding of the cellular bases of learning and memory and the consideration of therapies targeted to the CREB pathway.
Open Access
Noncanonical cytoplasmic poly(A) polymerases regulate RNA levels, alternative RNA processing, and synaptic plasticity but not hippocampal-dependent behaviours
(Informa UK Limited, 2020-10-12) Mansur, Fernanda; Alarcon, Juan Marcos; Stackpole, Emily E.; Wang, Ruijia; Richter, Joel D.
Noncanonical poly(A) polymerases are frequently tethered to mRNA 3' untranslated regions and regulate poly(A) tail length and resulting translation. In the brain, one such poly(A) polymerase is Gld2, which is anchored to mRNA by the RNA-binding protein CPEB1 to control local translation at postsynaptic regions. Depletion of CPEB1 or Gld2 from the mouse hippocampus results in a deficit in long-term potentiation (LTP), but only depletion of CPEB1 alters animal behaviour. To test whether a related enzyme, Gld4, compensates for the lack of Gld2, we separately or simultaneously depleted both proteins from hippocampal area CA1 and again found little change in animal behaviour, but observed a deficit in LTP as well as an increase in long-term depression (LTD), two forms of protein synthesis-dependent synaptic plasticity. RNA-seq data from Gld2, Gld4, and Gld2/Gld4-depleted hippocampus show widespread changes in steady state RNA levels, alternative splicing, and alternative poly(A) site selection. Many of the RNAs subject to these alterations encode proteins that mediate synaptic function, suggesting a molecular foundation for impaired synaptic plasticity.