Fluoxetine and ketamine trigger the p75NTR proteolytic pathway and enhance extinction memory and brain plasticity through p75NTR.

BACKGROUND: Diverse antidepressants were recently described to bind to TrkB and drive a positive allosteric modulation of endogenous BDNF. Although neurotrophins such as BDNF can bind to the p75 neurotrophin receptor (p75NTR), their precursors are the high affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a cross-like conformation dimer and carry a cholesterol-recognition and alignment consensus in the transmembrane domain. Since such qualities were found crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR. METHODS: ELISA-based binding assay and NMR spectroscopy were accomplished to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to address whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase-dependent p75NTR proteolysis, and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75KO mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verifying how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male WT mice and rats. RESULTS: Antidepressants were found binding to p75NTR, FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes. CONCLUSION: We thus hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain ability for remodeling.

Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics.

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.

Network Asynchrony Underlying Increased Broadband Gamma Power.

Synchronous activity of cortical inhibitory interneurons expressing parvalbumin (PV) underlies expression of cortical γ rhythms. Paradoxically, deficient PV inhibition is associated with increased broadband γ power in the local field potential. Increased baseline broadband γ is also a prominent characteristic in schizophrenia and a hallmark of network alterations induced by NMDAR antagonists, such as ketamine. Whether enhanced broadband γ is a true rhythm, and if so, whether rhythmic PV inhibition is involved or not, is debated. Asynchronous and increased firing activities are thought to contribute to broadband power increases spanning the γ band. Using male and female mice lacking NMDAR activity specifically in PV neurons to model deficient PV inhibition, we here show that neuronal activity with decreased synchronicity is associated with increased prefrontal broadband γ power. Specifically, reduced spike time precision and spectral leakage of spiking activity because of higher firing rates (spike "contamination") affect the broadband γ band. Desynchronization was evident at multiple time scales, with reduced spike entrainment to the local field potential, reduced cross-frequency coupling, and fragmentation of brain states. Local application of S(+)-ketamine in (control) mice with intact NMDAR activity in PV neurons triggered network desynchronization and enhanced broadband γ power. However, our investigations suggest that disparate mechanisms underlie increased broadband γ power caused by genetic alteration of PV interneurons and ketamine-induced power increases in broadband γ. Our study confirms that enhanced broadband γ power can arise from asynchronous activities and demonstrates that long-term deficiency of PV inhibition can be a contributor.SIGNIFICANCE STATEMENT Brain oscillations are fundamental to the coordination of neuronal activity across neurons and structures. γ oscillations (30-80 Hz) have received particular attention through their association with perceptual and cognitive processes. Synchronous activity of inhibitory parvalbumin (PV) interneurons generates cortical γ oscillation, but, paradoxically, PV neuron deficiency is associated with increases in γ oscillations. We here reconcile this conundrum and show how deficient PV inhibition can lead to increased and asynchronous excitatory firing, contaminating the local field potential and manifesting as increased γ power. Thus, increased γ power does not always reflect a genuine rhythm. Further, we show that ketamine-induced γ increases are caused by separate network mechanisms.

Hijacking of hippocampal-cortical oscillatory coupling during sleep in temporal lobe epilepsy.

Memory impairment is the most common cognitive deficit in patients with temporal lobe epilepsy (TLE). This type of epilepsy is currently regarded as a network disease because of its brain-wide alterations in functional connectivity between temporal and extra-temporal regions. In patients with TLE, network dysfunctions can be observed during ictal states, but are also described interictally during rest or sleep. Here, we examined the available literature supporting the hypothesis that hippocampal-cortical coupling during sleep is hijacked in TLE. First, we look at studies showing that the coordination between hippocampal sharp-wave ripples (100-200 Hz), corticothalamic spindles (9-16 Hz), and cortical delta waves (1-4 Hz) during nonrapid eye movement (NREM) sleep is critical for spatial memory consolidation. Then, we reviewed studies showing that animal models of TLE display precise coordination between hippocampal interictal epileptiform discharges (IEDs) and spindle oscillations in the prefrontal cortex. This aberrant oscillatory coupling seems to surpass the physiological ripple-delta-spindle coordination, which could underlie memory consolidation impairments. We also discuss the role of rapid eye movement (REM) sleep for local synaptic plasticity and memory. Sleep episodes of REM provide windows of opportunity for reactivation of expression of immediate early genes (i.e., zif-268 and Arc). Besides, hippocampal theta oscillations during REM sleep seem to be critical for memory consolidation of novel object place recognition task. However, it is still unclear which extend this particular phase of sleep is affected in TLE. In this context, we show some preliminary results from our group, suggesting that hippocampal theta-gamma phase-amplitude coupling is exacerbated during REM in a model of basolateral amygdala fast kindling. In conclusion, there is an increasing body of evidence suggesting that circuits responsible for memory consolidation during sleep seem to be gradually coopted and degraded in TLE. This article is part of the Special Issue "NEWroscience 2018".

Method to assess the mismatch between the measured and nominal parameters of transcranial magnetic stimulation devices.

BACKGROUND: Small variations in TMS parameters, such as pulse frequency and amplitude may elicit distinct neurophysiological responses. Assessing the mismatch between nominal and experimental parameters of TMS stimulators is essential for safe application and comparisons of results across studies. NEW METHOD: A search coil was used to assess exactness and precision errors of amplitude and timing parameters such as interstimulus interval, the period of pulse repetition, and intertrain interval of TMS devices. The method was validated using simulated pulses and applied to six commercial stimulators in single-pulse (spTMS), paired-pulse (ppTMS), and repetitive (rTMS) protocols, working at several combinations of intensities and frequencies. RESULTS: In a simulated signal, the maximum exactness error was 1.7% for spTMS and the maximum precision error 1.9% for ppTMS. Three out of six TMS commercial devices showed exactness and precision errors in spTMS amplitude higher than 5%. Moreover, two devices showed amplitude exactness errors higher than 5% in rTMS with parameters suggested by the manufactures. COMPARISON WITH EXISTING METHODS: Currently available tools allow characterization of induced electric field intensity and focality, and pulse waveforms of a single TMS pulse. Our method assesses the mismatch between nominal and experimental values in spTMS, ppTMS and rTMS protocols through the exactness and precision errors of amplitude and timing parameters. CONCLUSION: This study highlights the importance of evaluating the physical characteristics of TMS devices and protocols, and provides a method for on-site quality assessment of multiple stimulation protocols in clinical and research environments.

Closed-loop optogenetic strategy in experimental epilepsy: how affordable Is the implementation of this emergent technique? / Estratégia optogenética de alça fechada na epilepsia experimental: quão acessível é a implementação desta técnica emergente? / Estrategia optogenética de bucle cerrado en la epilepsia experimental: ¿cuán asequible es la aplicación de esta técnica emergente?

To explore complex mechanisms in the brain is an expensive task, which requires a combination of technological development and theoretical advances in neurobiology. In fact, it still is extremely challenging to diagnose accurately and treat some neurological diseases like drug-resistant epilepsy. In some cases, pharmacological interventions, electrical stimulation and surgery in epilepsy can be the specific cause of cognitive impairments and/or psychiatric comorbidities. Therefore, developing more selective strategies to control events produced by abnormal brain activity is mandatory. Our objective was to synthesize and organize information from the literature about the fundamental concepts that support the combination of optogenetics and closed-loop strategies in experimental epilepsy. We also sought to discuss how affordable would be the implementation of these emergent techniques. For this purpose, we first reviewed the literature on the closed-loop optogenetics and its applications for experimental epilepsy. Then, in order to evaluate the feasibility of this approach, we organized the information available in the literature on the materials necessary, and their respective costs. The combination of real-time detection and optogenetics has enormous potential to produce breakthroughs in neuroscience and its use for seizure control will certainly open new possibilities for more effective treatments of epilepsy. Overall, the costs of implementing a robust system with a high temporal precision and accuracy for detection and interference in seizures are relatively small. In addition, costs can be even lower if researchers choose open source hardware tools and software. Therefore, implementation of optogenetics with strategies of closed-loop in experimental epilepsy seems to demand more joint interdisciplinary efforts and innovative scientific questions than financial resources.

Investigar mecanismos complexos no cérebro é uma tarefa dispendiosa, que requer a combinação de desenvolvimento tecnológico e avan- ços teóricos em neurobiologia. De fato, realizar diagnósticos e tratar apropriadamente desordens neurológicas, como epilepsia resistente ao tratamento farmacológico, ainda é um grande desafio. Em alguns casos, as intervenções farmacológicas, a estimulação elétrica e a cirúrgica em epilepsia podem ser as próprias causadoras de prejuízos cognitivos e/ou comorbidades psiquiátricas. Portanto, é mandatório o desenvolvi- mento de estratégias mais seletivas para controlar eventos gerados por atividade anormal do encéfalo. Nosso objetivo foi sintetizar e organizar informações da literatura sobre os conceitos fundamentais que dão suporte à combinação de optogenética e estratégias de alça fechada em epilepsia experimental. Além disso, objetivamos discutir o quão financeiramente acessível seria a implementação dessas novas técnicas. Para isso, primeiramente revisamos a literatura sobre optogenética e estratégias de alça fechada e suas aplicações para epilepsia experimental. Em seguida, com o objetivo de avaliar quão acessível seria essa abordagem, organizamos a informação disponível na literatura sobre os materiais necessários e seus respectivos custos. A combinação de detecção em tempo real e optogenética tem um potencial enorme para produzir avanços em neurociências e seu uso para o controle de crises certamente abrirá novas possibilidades para tratamentos mais eficientes da epilepsia. Em geral, os custos para a implementação de um sistema robusto, com alta precisão temporal e acurácia para detecção e interferência em crises são relativamente pequenos. Além disso, eles podem ser ainda menores se os pesquisadores optarem por ferramentas de hardware e software de fonte aberta. Portanto, a implementação da optogenética com estratégia de alça fechada em epilepsia experimental parece demandar mais esforços interdisciplinares conjuntos e perguntas científicas inovadoras do que recursos financeiros.

Investigar los mecanismos complejos en el cerebro es una tarea costosa, que requiere una combinación de desarrollo tecnológico y los avances teóricos en la neurobiología. De hecho, todavía es um gran desafio diagnosticar con precisión y tratar apropriadamente trastornos neurológicos como la epilepsia resistente al tratamiento farmacológico. En algunos casos, las intervenciones farmacológicas, la estimulación eléctrica y la ciru- gía pueden ser por sí mismas la causa de los deterioros cognitivos y/o comorbilidades psiquiátricas. Por esta razon, es obligatorio el desarrollo de estrategias más selectivas para controlar los eventos producidos por la actividad cerebral anormal. Nuestro objetivo fue sintetizar y organizar la información de la literatura acerca de los conceptos fundamentales que soportan la combinación de la optogenética y estrategias de bucle cerrado en la epilepsia experimental. Además, tratamos de discutir cuán asequible sería la implementación de estas nuevas técnicas. Para ello, primero hemos revisado la literatura sobre la optogenética y las estrategias de bucle cerrado y sus aplicaciones en la epilepsia experimental. Luego, con el fin de evaluar cómo sería este enfoque económico, organizamos la información disponible en la literatura sobre los materiales requeridos y sus costos. La combinación de la detección en tiempo real y la optogenética tiene un enorme potencial para producir avances en la neurociencia y su uso para control de las crisis epilépticas sin duda abrirá nuevas posiblidades para tratamientos más eficaces de la epilepsia. Generalmente, los costos de implementación de un sistema robusto con una alta precisión temporal y la exactitud de detección y de interfencia en las convulsiones son relativamente pequeños. Además, los costos pueden ser incluso más bajos si los pesquisadores eligierenherramientas de hardware y software de código abierto y libre acceso. Por lo tanto, la aplicación de la optogenética con la estrategia de bucle cerrado en la epilepsia experimental parece exigir más esfuerzos interdisciplinarios conjuntos y preguntas científicas innovadoras que recursos financieros.