Biology subjects

Castren, E.

Publications and source records attributed to Castren, E..

At least 19 recordsLinked to original sources

bioRxiv2026

BDNF and glucocorticoids modulate neuroplasticity via direct interaction between TRKB and glucocorticoid receptors

The overlapping effects on neuronal plasticity of acute increase in glucocorticoid levels and the BDNF-TRKB signaling indicate a deep interconnection between the two pathways. Moreover, chronic stress with elevated glucocorticoids levels and downregulation of TRKB signaling associated with reduced BDNF are both involved in the pathophysiology of different psychiatric disorders. However, the mechanism by which TRKB and glucocorticoid receptors are recruited together in the modulation of neuronal plasticity is not clear yet. In this study we investigated the molecular mechanisms underlying the interplay of glucocorticoids and TRKB signaling in vitro and in vivo. We found that although not binding directly to TRKB, glucocorticoids promote TRKB dimerization and signaling similarly to BDNF. Moreover, the glucocorticoid receptor physically interacts with TRKB, modulating its dimerization and activity both in presence and in absence of glucocorticoids and contributing to TRKB-mediated plasticity. The transmembrane domain of TRKB is important for the interaction and for mediating the behavioral effects of TRKB and glucocorticoid receptor modulation, suggesting at least a partial overlap between the two signaling pathways. These results shed light on the interconnected effects of glucocorticoid and TRKB signaling highlighting the need for a more comprehensive understanding of the role and the dysfunction of different players contributing to synaptic plasticity.

neuroscience↗

bioRxiv2025

A Surgical Protocol for a Large, Resealable Cranial Window Enabling Longitudinal, Multi-Modal Electrophysiological Recordings of the Mouse Default Mode Network

The Default Mode Network (DMN) is a central large-scale brain network implicated in a range of cognitive functions and neuropsychiatric disorders, such as major depressive disorder (MDD). Studying the DMNs complex dynamics in animal models provides invaluable insights into its function in both healthy and pathological states. However, performing a stable, long-term, and large-scale electrophysiological recordings from the multiple, deep, and distributed nodes of the DMN in awake, behaving mice has been a significant challenge. Here, we present a novel, two-phase surgical protocol developed to create a large (4x7.6 mm), durable, and resealable cranial window in mice. The procedure is designed to preserve the integrity of the dura mater, which is paramount for long-term brain health and recording stability. This window facilitates repeated, longitudinal recordings from over 1,000 electrodes simultaneously by combining surface-level micro-electrocorticography ({micro}ECoG) with two high-density intracranial electrode probes, allowing unprecedented access to the DMN. This technique provides a robust platform for multi-modal, multi-scale interrogation of network-wide electrophysiological dynamics over several weeks, opening new avenues for investigating the neuroplastic changes underlying the pathophysiology of brain disorders and for evaluating the chronic effects of novel therapeutics. SUMMARYThis protocol describes a two-phase surgical method to create a large, resealable, dura-sparing cranial window in mice. This technique enables chronic, multi-modal electrophysiological recordings from distributed, deep brain networks, such as the Default Mode Network, over several weeks.

neuroscience↗

bioRxiv2025

Low-dimensional brain-symptom associations delineate depression phenotypes with distinct connectivity biomarkers and symptom profiles

Depression is neurobiologically and clinically heterogeneous. New approaches using resting-state functional MRI (rs-fMRI) functional connectivity (FC) data have modeled the neural basis of depression heterogeneity and revealed unique neural phenotypes. Yet, no studies have identified depression phenotypes from electrophysiological magnetoencephalography (MEG) data although MEG measures human brain dynamics at millisecond precision. We demonstrate here unique depression phenotypes based on MEG-oscillation FC. We collected resting-state MEG, MRI, and clinical symptom data from 263 patients with unipolar depression and 75 healthy controls. We assessed MEG-FC with two oscillatory coupling-mode measures that are fundamental for information processing. To define normative phenotypes, we computed their latent-space low-dimensional brain-symptom associations, and used these components to identify phenotypes using unsupervised machine learning. We identified five stable depression phenotypes that were characterized by unique symptom profiles and distinct spectral patterns. Our results demonstrate new neural underpinnings of depression heterogeneity and reveal unique neural phenotypes with potential personalized diagnostic value.

neuroscience↗

bioRxiv2024

Cleavage of the TrkB-FL Receptor During Epileptogenesis: Insights from a Kainic Acid-Induced Model of Epilepsy and Human Samples

AO_SCPLOWBSTRACTC_SCPLOWBrain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and plasticity. In epilepsy, BDNF exhibits a dual role, exerting both antiepileptic and pro-epileptic effects. The cleavage of its main receptor, full-length tropomyosin-related kinase B (TrkB-FL), was suggested to occur in status epilepticus (SE) in vitro. Moreover, under excitotoxic conditions, TrkB-FL was found to be cleaved, resulting in the formation of a new intracellular fragment, TrkB-ICD. Thus, we hypothesized that TrkB-FL cleavage and TrkB-ICD formation could represent an uncovered mechanism in epilepsy. We used a rat model of mesial temporal lobe epilepsy (mTLE) induced by kainic acid (KA) to investigate TrkB-FL cleavage and TrkB-ICD formation during SE and established epilepsy (EE). Animals treated with 10 mg/kg of KA exhibited TrkB-FL cleavage during SE, with hippocampal levels of TrkB-FL and TrkB-ICD correlating with seizure severity. Notably, TrkB-FL cleavage and TrkB-ICD formation were also detected in animals with EE, which exhibited spontaneous recurrent convulsive seizures, neuronal death, mossy fiber sprouting, and long-term memory impairment. Importantly, hippocampal samples from patients with refractory epilepsy also showed TrkB-FL cleavage with increased TrkB-ICD levels. Additionally, overexpression of TrkB-ICD in the hippocampus of healthy rodents resulted in long-term memory impairment. Our findings suggest that TrkB-FL cleavage and the subsequent TrkB-ICD production occur throughout epileptogenesis, with the extent of cleavage correlating positively with seizure occurrence. Moreover, we found that TrkB-ICD impairs memory. This work uncovers a novel mechanism in epileptogenesis that could serve as a potential therapeutic target in mTLE, with implications for preserving cognitive function.

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bioRxiv2024

Chronic treatment with fluoxetine downregulates mitochondrial activity in parvalbumin interneurons of prefrontal cortex

Chronic treatment with fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI), is known to promote neural plasticity. The role of fluoxetine in plasticity has been particularly tied to parvalbumin-positive interneurons (PV-INs), which are critical regulators of inhibitory tone and synaptic plasticity. Our previous studies have highlighted behavioral plasticity and gene expression changes in the visual cortex and hippocampus after chronic treatment with fluoxetine. However, the impact of fluoxetine treatment on gene expression and neuronal function in the prefrontal cortex (PFC) remains unclear. This study aimed to investigate the effects of chronic fluoxetine treatment on PV-INs in the PFC. Using Translating Ribosome Affinity Purification (TRAP), we found that fluoxetine treatment downregulated pathways involved in mitochondrial energy production, including multiple steps of the respiratory chain. Upregulated genes were associated with phosphatase activity, voltage-gated potassium channels, and amino acid transmembrane transport. Mitochondrial analysis for sorted cells demonstrated mitochondrial membrane potential was reduced in PV-INs, but increased in non-PV-INs in the PFC. These observations indicate altered mitochondrial dynamics between the cell types and reduced mitochondrial activity in PV-INs, potentially contributing to their disinhibition. Immunohistochemical analyses further demonstrated reduced PV expression and weakened perineuronal nets in specific PFC regions, suggesting elevated plasticity, and potentially explaining the modulation of fear and anxiety-related behaviors that were previously observed. Our results underscore the differential impact of chronic fluoxetine on gene expression and mitochondrial function in PV-INs, suggesting region-specific disinhibition and enhanced synaptic plasticity in the PFC.

neuroscience↗

bioRxiv2024

The BDNF/TrkB pathway in Somatostatin-expressing neurons suppresses cocaine-seeking behaviour

Cocaine addiction is a highly debilitating condition consisting of compulsive self-administration and seek for the substance of abuse, and its most challenging feature is the high rate of relapse. Addiction and relapse share similarities with neural plasticity which acts through the Brain-Derived Neurotrophic Factor and its receptor TrkB. Somatostatin (SST) expressing interneurons are involved in neuronal plasticity and are important in modulating cocaine-seeking behaviour in mice. We tested the role of TrkB in Somatostatin (SST)-expressing neurons in the extinction of cocaine-seeking behaviour, using mice in which TrkB has been knocked out specifically in SST neurons. We have observed that in these mice, once a cocaine-conditioned place preference is acquired, its extinction through seven days of extinction training is impaired, showing how this process relies on neural plasticity in SST neurons. When we promoted plasticity during extinction training using a light-activable TrkB in SST neurons in the prefrontal cortex of cocaine-conditioned mice, relapse of cocaine-seeking was prevented. Our data identify the critical role of TrkB-mediated plasticity within SST neurons in the extinction of and relapse to cocaine addiction.

neuroscience↗

bioRxiv2022

Activation of TrkB in Parvalbumin interneurons is required for the promotion of reversal learning in spatial and fear memory by antidepressants

Critical period-like plasticity (iPlasticity) can be reinstated in the adult brain by several interventions, including drugs and optogenetic modifications. We have demonstrated that a combination of iPlasticity with optimal training improves behaviors related to neuropsychiatric disorders. In this context, the activation of TrkB, a receptor for BDNF, in Parvalbumin positive (PV+) interneurons has a pivotal role in cortical network changes. However, it is unknown if the activation of TrkB in PV+ interneurons is important for other plasticity-related behaviors, especially for learning and memory. Here, using mice with heterozygous conditional TrkB deletion in PV+ interneurons (PV-TrkB hCKO) in Intellicage and fear erasure paradigms, we show that chronic treatment with fluoxetine, a widely prescribed antidepressant drug that is known to promote the activation of TrkB, enhances behavioral flexibility in spatial and fear memory, largely depending on the expression of the TrkB receptor in PV+ interneurons. In addition, hippocampal long-term potentiation (LTP) was enhanced by chronic treatment with fluoxetine in wild-type mice, but not in PV-TrkB hCKO mice. Transcriptomic analysis of PV+ interneurons after fluoxetine treatment indicated intrinsic changes in synaptic formation and downregulation of enzymes involved in perineuronal net (PNN) formation. Consistently, immunohistochemistry has shown that the fluoxetine treatment alters PV expression and reduces PNNs in PV+ interneurons, and here we show that TrkB expression in PV+ interneurons is required for these effects. Together, our results provide molecular and network mechanisms for the induction of critical period-like plasticity in adulthood.

neuroscience↗

bioRxiv2022

Mutation in the TRKB cholesterol recognition site that blocks antidepressant binding does not influence the basal or BDNF-stimulated activation of TRKB

Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol-recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressants drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Y433F). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Y433F mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Y433F mutant mice (hTRKB.Y433F) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Y433F mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Y433F mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Y433F mutants, making them an interesting mouse model for antidepressant research.

neuroscience↗

bioRxiv2022

Nitric oxide-induced tyrosine nitration of TrkB impairs BDNF signaling and restrains neuronal plasticity

Nitric oxide has been long recognized as an important modulator of neural plasticity, but characterization of the molecular mechanisms involved - specially the guanylyl cyclase-independent ones - has been challenging. There is evidence that NO could modify BDNF-TRKB signaling, a key mediator of neuronal plasticity. However, the mechanism underlying the interplay of NO and TRKB remains unclear. Here we show that nitric oxide induces nitration of the tyrosine 816 in the TRKB receptor in vivo and in vitro, and that post-translational modification inhibits TRKB phosphorylation and binding of phospholipase C{gamma}1 (PLC{gamma}1) to this same tyrosine residue. Additionally, nitration triggers clathrin-dependent endocytosis of TRKB through the adaptor protein AP2M and ubiquitination, thereby increasing translocation of TRKB away from the neuronal surface and directing it towards lysosomal degradation. Accordingly, inhibition of nitric oxide increases TRKB phosphorylation and TRKB-dependent neurite branching in neuronal cultures. In vivo, chronic inhibition of neuronal nitric oxide synthase (nNOS) dramatically reduced TRKB nitration and facilitated TRKB signaling in the primary visual cortex, and promoted a shift in ocular dominance upon monocular deprivation in the visual cortex - an indicator of increased plasticity. Altogether, our data describe and characterize a new molecular brake on plasticity, namely nitration of TRKB receptors. Significance statementWe described the nitration of TRKB receptors at the tyrosine residue 816 as a new post-translational modification (PTM) that restrains the signaling of the neurotrophic factor BDNF in neurons. This new PTM leads to endocytosis and degradation of the TRKB receptors. Intriguingly, this mechanism is tonically active under physiological conditions in vivo, and it is important for restricting ocular dominance plasticity in the visual cortex. This mechanism directly links two major systems involved in brain plasticity, BDNF/TRKB and nitric oxide. Our data provides a model for how NO production from nNOS can compromise TRKB function, and for the effects of nNOS inhibitors promoting plasticity.

neuroscience↗

bioRxiv2022

Ketamine and its metabolite 2R,6R-hydroxynorketamine promote ocular dominance plasticity and release TRKB from inhibitory control without changing perineuronal nets enwrapping parvalbumin interneurons

Ketamine has been described as a fast-acting antidepressant, exerting effects in depressed patients and in preclinical models with a rapid onset of action. The typical antidepressant fluoxetine is known to induce plasticity in the adult rodent visual cortex, as assessed by a shift in ocular dominance, a classical model of brain plasticity, and a similar effect has been described for ketamine and its metabolite 2R,6R-hydroxynorketamine (R,R-HNK). Here, we demonstrate that ketamine (at 3 or 20 mg/kg) and R,R-HNK facilitated the shift in ocular dominance in monocularly deprived mice, after 3 injections, throughout the 8-days regimen. Notably, the comparison between the treatments indicates a higher effect size of R,R-HNK compared to ketamine. Treatment with ketamine or R,R-HNK failed to influence the levels of perineuronal nets (PNNs) surrounding parvalbumin-positive interneurons. However, we observed in vitro that both ketamine and R,R-HNK are able to disrupt the tropomyosin-related kinase B (TRKB) interaction with the protein tyrosine phosphatase sigma (PTP{sigma}), which upon binding to PNNs dephosphorylates TRKB. These results support a model where diverse drugs promote the reinstatement of juvenile-like plasticity by directly binding TRKB and releasing it from PTP{sigma} regulation, without necessarily affecting PNNs deposits.

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bioRxiv2021

SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington's disease progression

BackgroundHuntingtons disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Mutations in BDNF receptor SorCS2 were recently identified in HD patients. Our study investigates the role of SorCS2 in MSNs biology and in HD progression. MethodsWe derived a double transgenic line by crossbreeding SorCS2 deficient (KO) mice with the HD mouse model R6/1. Subsequently, we characterized the SorCS2 KO; R6/1 line by a set of behavioral and biochemical studies to evaluate phenotypes related to HD. Moreover, in combination with electrophysiology and super resolution microscopy techniques, we addressed the molecular mechanism by which SorCS2 controls synaptic activity in MSNs neurons. ResultsWe show that SorCS2 is expressed in MSNs with reduced levels in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. However, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice. ConclusionsWe formulate a novel molecular mechanism by which SorCS2 acts as a molecular switch. SorCS2 targets TrkB and GluN2B into postsynaptic densities to enable BDNF signaling and NMDAR dependent neurotransmission in the dorsal striatum. Remarkably, the binding between SorCS2 and TrkB or GluN2B, respectively, is mutually exclusive and controlled by BDNF. This mechanism provides an explanation why deficient SorCS2 signaling severely aggravates HD progression in mice. Moreover, we provide evidence that this finding might represent a general mechanism of SorCS2 signaling found in other brain areas, thus increasing its relevance for other neurological and psychiatric impairments.

neuroscience↗

bioRxiv2021

Facilitation of TRKB activation by the angiotensin II receptor type-2 (AT2R) agonist C21

Blockers of angiotensin II type-1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type-2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1-10M/15min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10M/15min or 3 days) facilitated the effect of BDNF (0.1ng/ml/15min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.

pharmacology and toxicology↗

bioRxiv2021

Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro

Background and PurposeRepurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Experimental ApproachSeveral antidepressant drugs and antipsychotic drugs with different primary mechanisms of action were tested in ACE2/TMPRSS2-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7 and B.1.351. Key ResultsSeveral clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the (B.1) lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudo viruses with N501Y, K417N, and E484K spike mutations, and the VoC-1 (B.1.1.7) and VoC-2 (B.1.351) variants of SARS-CoV-2. Conclusion and ImplicationsOur study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection including different variants of concern.

pharmacology and toxicology↗

bioRxiv2021

Perineuronal net receptor PTPσ regulates retention of memories

Perineuronal nets (PNNs) have an important physiological role in retention of learning by restricting cognitive flexibility. Their deposition peaks after developmental periods of intensive learning, usually in late childhood, and they help in long-term preservation of new acquired skills and information. Modulation of PNN function by various techniques enhances plasticity and regulates retention of memories, which may be beneficial when memory persistence entails negative symptoms such as post-traumatic stress disorder (PTSD). In this study, we investigated the role of PTP{sigma} (receptor-type tyrosine-protein phosphatase S, a phosphatase that is activated by binding of chondroitin sulfate proteoglycans from PNNs) in retention of memories using novel object recognition and fear conditioning rodent models. We observed that mice haploinsufficient for PTPRS gene (PTP{sigma}+/-), although having improved short-term object recognition memory, display impaired long-term memory in both novel object recognition and fear conditioning paradigm, as compared to WT littermates. However, PTP{sigma}+/- mice didnt show any differences in behavioral tests that do not heavily rely on cognitive flexibility, such as elevated plus maze, open field, marble burying and forced swimming test. Since PTP{sigma} has been shown to interact with and dephosphorylate TRKB, we investigated activation of this receptor and its downstream pathways in limbic areas known to be associated with memory. We found that phosphorylation of TRKB and PLC{gamma} are increased in the hippocampus, prefrontal cortex and amygdala of PTP{sigma}+/- mice, but other TRKB-mediated signaling pathways are not affected. Our data suggest that disruption of PNN-PTP{sigma} complex facilitates short-term memory by promoting TRKB phosphorylation in different brain areas, but that PTP{sigma} activity is required for the retention of long-term memories. Inhibition of PTP{sigma} or disruption of PNN-PTP{sigma}-TRKB complex might be a potential target for disorders where negative modulation of the acquired memories can be beneficial. Conflict of interestThe authors declare no conflict of interest. FundingThis work was supported by Doctoral Program in Integrative Life Science, Jalmari ja Rauha Ahokkaan Saatio grant, Centre for International Mobility (CIMO) Grant TM-16-10112, and by grants from European Research Council (#322742), EU Joint Programme - Neurodegenerative Disease Research (JPND) CircProt (#301225 and #643417), Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, and the Academy of Finland (#294710 and #307416). None of the funders had a role in the data acquisition, analysis or manuscript preparation. Author contributionsPC, CB and EC designed the study; AL, PC and CB performed the experiments and analyzed the data; AL wrote the manuscript draft; AL, PC, CB and EC revised the manuscript. Contribution to the Field StatementPlasticity of neuronal networks increases brains ability to adapt and it is compromised in various conditions including psychiatric diseases, brain injuries, neurodevelopmental and neurodegenerative disorders. Perineuronal nets, through their receptor PTP{sigma} restrict neuronal plasticity in adult brain, which is considered important for the retention of long-term memories. We have previously shown that this restricted plasticity is mediated by inhibition by PTP{sigma} of the TRKB neurotrophin receptor. We have now investigated the biochemical and behavioral phenotype of mice with reduced PTP{sigma} expression. We observed that PTP{sigma}+/- mice have increased phosphorylation of TRKB and its downstream partner PLC{gamma}1 in the prefrontal cortex, hippocampus and amygdala, demonstrating chronic overactivation of plasticity-related pathways. Consistently, PTP{sigma}+/- mice demonstrated facilitated learning but impaired long-term memory retention. Unexpectedly, long-term memory of PTP{sigma}+/- mice was impaired, suggesting that perneuronal net-stimulated PTP{sigma} activity is important in memory retention. This effect of neuronal "hyperplasticity" induced by PTP{sigma} knockout may be both beneficial and harmful in the treatment of human patients, which should be taken into account when developing therapeutic strategies.

neuroscience↗

bioRxiv2021

Optical activation of TrkB neurotrophin receptor in mouse ventral hippocampus promotes plasticity and facilitates fear extinction

Successful extinction of traumatic memories depends on neuronal plasticity in the fear extinction network. However, the mechanisms involved in the extinction process remain poorly understood. Here, we investigated the fear extinction network by using a new optogenetic technique that allows temporal and spatial control of neuronal plasticity in vivo. We optimized an optically inducible TrkB (CKII-optoTrkB), the receptor of the brain-derived neurotrophic factor, which can be activated upon blue light exposure to increase plasticity specifically in pyramidal neurons. The activation of CKII-optoTrkB facilitated the induction of LTP in Schaffer collateral-CA1 synapses after brief theta-burst stimulation and increased the expression of FosB in the pyramidal neurons of the ventral hippocampus, indicating enhanced plasticity in that brain area. We showed that optical stimulation of the CA1 region of the ventral hippocampus during fear extinction training led to an attenuated conditioned fear memory. This was a specific effect only observed when combining extinction training with CKII-optoTrkB activation, and not when using either intervention alone. Thus, TrkB activation in ventral CA1 pyramidal neurons promotes a state of neuronal plasticity that allows extinction training to guide neuronal network remodeling to overcome fear memories. Our methodology is a powerful tool to induce neuronal network remodeling in the adult brain, and can attenuate neuropsychiatric symptoms caused by malfunctioning networks.

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bioRxiv2020

Chondroitinase and antidepressants promote plasticity by releasing TRKB from dephosphorylating control of PTPσ in parvalbumin neurons

Perineuronal nets (PNNs) are an extracellular matrix structure rich in chondroitin sulphate proteoglycans (CSPGs) which preferentially encase parvalbumin-containing (PV+) interneurons. PNNs restrict cortical network plasticity but the molecular mechanisms involved are unclear. We found that reactivation of ocular dominance plasticity in the adult visual cortex induced by chondroitinase (chABC)-mediated PNN removal requires intact signaling by the neurotrophin receptor TRKB in PV+ neurons. Additionally, we demonstrate that chABC increases TRKB phosphorylation (pTRKB), while PNN component aggrecan attenuates BDNF-induced pTRKB in cortical neurons in culture. We further found that protein tyrosine phosphatase sigma (PTP{sigma}, PTPRS), receptor for CSPGs, interacts with TRKB and restricts TRKB phosphorylation. PTP{sigma} deletion increases phosphorylation of TRKB in vitro and in vivo in male and female mice, and juvenile-like plasticity is retained in the visual cortex of adult PTP{sigma} deficient mice (PTP{sigma}+/-). The antidepressant drug fluoxetine, which is known to promote TRKB phosphorylation and reopen critical period-like plasticity in the adult brain, disrupts the interaction between TRKB and PTP{sigma} by binding to the transmembrane domain of TRKB. We propose that both chABC and fluoxetine reopen critical period-like plasticity in the adult visual cortex by promoting TRKB signaling in PV+ neurons through inhibition of TRKB dephosphorylation by the PTP{sigma}-CSPG complex. Significance statementCritical period-like plasticity can be reactivated in the adult visual cortex through disruption of perineuronal nets (PNNs) by chondroitinase treatment, or by chronic antidepressant treatment. We now show that the effects of both chondroitinase and fluoxetine are mediated by the neurotrophin receptor TRKB in parvalbumin-containing (PV+) interneurons. We found that chondroitinase-induced visual cortical plasticity is dependent on TRKB in PV+ neurons. Protein tyrosine phosphatase type S (PTP{sigma}, PTPRS), a receptor for PNNs, interacts with TRKB and inhibits its phosphorylation, and chondroitinase treatment or deletion of PTP{sigma} increases TRKB phosphorylation. Antidepressant fluoxetine disrupts the interaction between TRKB and PTP{sigma}, thereby increasing TRKB phosphorylation. Thus, juvenile-like plasticity induced by both chondroitinase and antidepressant treatment is mediated by TRKB activation in PV+ interneurons.

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bioRxiv2020

Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats

It has been postulated that activation of NMDA receptors (NMDAr) and nitric oxide (NO) production in the hippocampus is involved in the behavioral consequences of stress. Stress triggers NMDAr-induced calcium influx in limbic areas, such as the hippocampus, which in turn activates neuronal NO synthase (nNOS). Inhibition of nNOS or NMDAr activity can prevent stress-induced effects in animal models, but the molecular mechanisms behind this effect are still unclear. In this study, cultured hippocampal neurons treated with NMDA or dexamethasone showed increased of DNA methyltransferase 3b (DNMT3b) mRNA expression, which was blocked by pre-treatment with nNOS inhibitor n{omega}-propyl-L-arginine (NPA). In rats submitted to the Learned Helplessness paradigm (LH), we observed that inescapable stress increased of DNMT3b mRNA expression at 1h and 24h in the hippocampus. The NOS inhibitors 7-NI and aminoguanidine (AMG) decreased the number of escape failures in LH, and counteracted the changes in hippocampal DNMT3b mRNA induced in this behavioral paradigm. Altogether, our data suggest that NO produced in response to NMDAr activation following stress upregulates DNMT3b in the hippocampus.

pharmacology and toxicology↗

bioRxiv2020

TrkB activation in Parvalbumin interneurons orchestrates cortical plasticity

Activation state of Parvalbumin (PV) interneurons regulates neuronal plasticity, driving the closure of developmental critical periods and alternating between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states are regulated through the activation of TrkB neurotrophin receptors. Activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing excitability of PV neurons. OptoTrkB activation induces changes in gene expression related to neuronal plasticity and excitability, and increases the phosphorylation of Kv3.1 channels. OptoTrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony and ocular dominance plasticity. Visual plasticity induced by fluoxetine was lost in mice lacking TrkB in PV neurons. Our data suggest a novel mechanism that dynamically regulates PV interneurons configuration state and orchestrates cortical networks during adulthood. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/063503v2_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@4c521corg.highwire.dtl.DTLVardef@a2ec04org.highwire.dtl.DTLVardef@353775org.highwire.dtl.DTLVardef@1cc0448_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗