Cleavage of the TrkB-FL receptor during epileptogenesis: insights from a kainic acid-induced model of epilepsy and human samples.

Brain-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.

Brain plasticity and neuroinflammatory protein biomarkers with circulating MicroRNAs as predictors of acute brain injury outcome - A prospective cohort study.

Background: Brain recovery mechanisms after injuries like aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI) involve brain plasticity, synaptic regeneration, and neuroinflammation. We hypothesized that serum levels of the p75 neurotrophic receptor (p75NTR) and associated signaling proteins, as well as differentially expressed (DE) microRNAs, could predict recovery outcomes irrespective of injury type.

Methods: A prospective patient cohort with ischemic stroke (IS, n = 30), aneurysmal subarachnoid hemorrhage (aSAH, n = 31), and traumatic brain injury (TBI, n = 13) were evaluated (total n = 74).

Somatostatin-Expressing Neurons in the Ventral Tegmental Area Innervate Specific Forebrain Regions and Are Involved in Stress Response.

Expanding knowledge about the cellular composition of subcortical brain regions demonstrates large heterogeneity and differences from the cortical architecture. Previously we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighboring dopaminergic neurons (Nagaeva et al., 2020).

An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis.

Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes.

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.

BDNF receptor TrkB as the mediator of the antidepressant drug action.

Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB has for a long time been recognized as a critical mediator of the antidepressant drug action, but BDNF signaling has been considered to be activated indirectly through the action of typical and rapid-acting antidepressants through monoamine transporters and glutamate NMDA receptors, respectively. However, recent findings demonstrate that both typical and the fast-acting antidepressants directly bind to TrkB and thereby allosterically potentiate BDNF signaling, suggesting that TrkB is the direct target for antidepressant drugs. Increased TrkB signaling particularly in the parvalbumin-expressing interneurons orchestrates iPlasticity, a state of juvenile-like enhanced plasticity in the adult brain.

Optical Activation of TrkB (E281A) in Excitatory and Inhibitory Neurons of the Mouse Visual Cortex.

The activation of tropomyosin receptor kinase B (TrkB), the receptor of brain-derived neurotrophic factor (BDNF), plays a key role in induced juvenile-like plasticity (iPlasticity), which allows restructuring of neural networks in adulthood. Optically activatable TrkB (optoTrkB) can temporarily and spatially evoke iPlasticity, and recently, optoTrkB (E281A) was developed as a variant that is highly sensitive to light stimulation while having lower basal activity compared to the original optoTrkB. In this study, we validate optoTrkB (E281A) activated in alpha calcium/calmodulin-dependent protein kinase type II positive (CKII) pyramidal neurons or parvalbumin-positive (PV) interneurons in the mouse visual cortex by immunohistochemistry.

Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity.

Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors.

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 sulfate 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 ABC (chABC)-mediated PNN removal requires intact signaling by the neurotrophin receptor TRKB in PV neurons.

A comprehensive p75 neurotrophin receptor gene network and pathway analyses identifying new target genes.

P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR's related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years.

Kainate Receptor Auxiliary Subunit NETO2-Related Cued Fear Conditioning Impairments Associate with Defects in Amygdala Development and Excitability.

NETO2 is an auxiliary subunit for kainate-type glutamate receptors that mediate normal cued fear expression and extinction. Since the amygdala is critical for these functions, we asked whether mice have compromised amygdala function. We measured the abundance of molecular markers of neuronal maturation and plasticity, parvalbumin-positive (PV), perineuronal net-positive (PNN), and double positive (PVPNN) cells in the amygdala.

A Critical Period for Prefrontal Network Configurations Underlying Psychiatric Disorders and Addiction.

The medial prefrontal cortex (mPFC) has been classically defined as the brain region responsible for higher cognitive functions, including the decision-making process. Ample information has been gathered during the last 40 years in an attempt to understand how it works. We now know extensively about the connectivity of this region and its relationship with neuromodulatory ascending projection areas, such as the dorsal raphe nucleus (DRN) or the ventral tegmental area (VTA).

Peripheral blood metabolome predicts mood change-related activity in mouse model of bipolar disorder.

Bipolar disorder is a major mental illness characterized by severe swings in mood and activity levels which occur with variable amplitude and frequency. Attempts have been made to identify mood states and biological features associated with mood changes to compensate for current clinical diagnosis, which is mainly based on patients' subjective reports. Here, we used infradian (a cycle > 24 h) cyclic locomotor activity in a mouse model useful for the study of bipolar disorder as a proxy for mood changes.

Immature-like molecular expression patterns in the hippocampus of a mouse model of dementia with Lewy body-linked mutant β-synuclein.

Aim: Maturation abnormalities of the brain cells have been suggested in several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorders, and epilepsy. In this study, we examined the expression patterns of neuronal maturation markers in the brain of a mouse model of dementia with Lewy body-linked mutant β-synuclein (βS), especially in the hippocampus, to explore whether such brain abnormalities occur in neurodegenerative disorders as well.

Methods: Quantitative PCR (qPCR) and immunohistochemical analyses were performed using the hippocampus of 14-month-old P123H βS transgenic (Tg) mice to evaluate the expression of molecular markers for maturation of dentate granule cells.

iPlasticity: Induced juvenile-like plasticity in the adult brain as a mechanism of antidepressants.

The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants (AD), including selective serotonin reuptake inhibitors (SSRI), function by gradually improving information processing within these networks. AD have been shown to induce a state of juvenile-like plasticity comparable to that observed during developmental critical periods: Such critical-period-like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals.

Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation.

Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment.

Circadian Gene Circuitry Predicts Hyperactive Behavior in a Mood Disorder Mouse Model.

Bipolar disorder, also known as manic-depressive illness, causes swings in mood and activity levels at irregular intervals. Such changes are difficult to predict, and their molecular basis remains unknown. Here, we use infradian (longer than a day) cyclic activity levels in αCaMKII (Camk2a) mutant mice as a proxy for such mood-associated changes.

Effects of PSA Removal from NCAM on the Critical Period Plasticity Triggered by the Antidepressant Fluoxetine in the Visual Cortex.

Neuronal plasticity peaks during critical periods of postnatal development and is reduced towards adulthood. Recent data suggests that windows of juvenile-like plasticity can be triggered in the adult brain by antidepressant drugs such as Fluoxetine. Although the exact mechanisms of how Fluoxetine promotes such plasticity remains unknown, several studies indicate that inhibitory circuits play an important role.

Evidence for Competition for Target Innervation in the Medial Prefrontal Cortex.

Inputs to sensory cortices are known to compete for target innervation through an activity-dependent mechanism during critical periods. To investigate whether this principle also applies to association cortices such as the medial prefrontal cortex (mPFC), we produced a bilateral lesion during early development to the ventral hippocampus (vHC), an input to the mPFC, and analyzed the intensity of the projection from another input, the basolateral amgydala (BLA). We found that axons from the BLA had a higher density of "en passant" boutons in the mPFC of lesioned animals.

Cell adhesion molecule contactin-associated protein 3 is expressed in the mouse basal ganglia during early postnatal stages.

Cell adhesion molecules play important roles in the development of the nervous system. Among the contactin-associated protein (Caspr; also known as Cntnap) family, which belongs to the neurexin superfamily of proteins, Caspr and Caspr2 are indispensable for the formation and maintenance of myelinated nerves. In contrast, a physiological role for Caspr3 remains to be elucidated.

Distinct effects of perinatal exposure to fluoxetine or methylmercury on parvalbumin and perineuronal nets, the markers of critical periods in brain development.

The in utero exposure to common chemical stressors, environmental pollutant methylmercury and antidepressant fluoxetine, results in behavioral impairments persistent into adulthood. Modulation of critical periods in brain development may alter proper network formation and lastingly impair brain function. To investigate whether early-life stressors can modulate critical periods, we analyzed the development of parvalbumin (PV) and perineuronal nets (PNNs) in the dentate gyrus and CA1 area of the hippocampus and the basolateral amygdala in mice perinatally exposed to either fluoxetine or methylmercury.

Nimodipine activates TrkB neurotrophin receptors and induces neuroplastic and neuroprotective signaling events in the mouse hippocampus and prefrontal cortex.

The L-type calcium channel blocker nimodipine improves clinical outcome produced by delayed cortical ischemia or vasospasm associated with subarachnoid hemorrhage. While vasoactive mechanisms are strongly implicated in these therapeutic actions of nimodipine, we sought to test whether nimodipine might also regulate neurotrophic and neuroplastic signaling events associated with TrkB neurotrophin receptor activation. Adult male mice were acutely treated with vehicle or nimodipine (10 mg/kg, s.

Distinctive behavioral and cellular responses to fluoxetine in the mouse model for Fragile X syndrome.

Fluoxetine is used as a therapeutic agent for autism spectrum disorder (ASD), including Fragile X syndrome (FXS). The treatment often associates with disruptive behaviors such as agitation and disinhibited behaviors in FXS. To identify mechanisms that increase the risk to poor treatment outcome, we investigated the behavioral and cellular effects of fluoxetine on adult Fmr1 knockout (KO) mice, a mouse model for FXS.