BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction.

Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations.

A Stage 1 Pilot Cohort Exploring the Use of EMDR Therapy as a Videoconference Psychotherapy During COVID-19 With Frontline Mental Health Workers: A Proof of Concept Study Utilising a Virtual Blind 2 Therapist Protocol.

Objective: The COVID-19 pandemic has had a major impact on the delivery of psychological treatment. Due to social distancing requirements, the provision moved to videoconferencing psychotherapy (VCP). There is a paucity of empirical data supporting the efficacy of EMDR therapy as a VCP. This stage 1 pilot study tested an EMDR therapy scripted protocol, such as Virtual Blind 2 Therapist (VB2Tr), on frontline mental health workers as a VCP regarding fitness for purpose, distinctiveness, relevance, and efficiency. Methods: A total of 24 participants were recruited for the study. The design included a one-session treatment intervention with pre, post, 1-month, and 6-month follow-up (FU) measurements. This treatment session used a "Blind 2 Therapist" EMDR therapy scripted protocol as videoconference psychotherapy that involves non-disclosure of traumatic memory. The research explored the treatment effect on the core characteristics of trauma memory, including subjective disturbance, belief systems, memory intensity (MI), vividness, and levels of emotionality. Additionally, the research explored participants' experiences of adverse and benevolent childhood experiences (ACEs/BCEs) during their childhood. Results: Regarding the four tests, namely, fitness for purpose, distinctiveness, relevance, and efficiency, results are favourably suggesting potential clinical benefits of using EMDR as videoconference psychotherapy. Although this is a proof-of-concept study showing positive results, no clinical population or control group was used. The purpose of the study is to explore the potential for scalability toward a larger clinical trial. The treatment intervention was achieved irrespective of either ACEs/BCEs during childhood. Conclusion: The research tentatively supports the case for EMDR therapy as a credible treatment when used as video conference psychotherapy and in using the Blind 2 Therapist protocol. However, more research is needed to scale toward a clinical trial. Clinical Trial Registration: Clinical Trial Registration: https://www.isrctn.com/ISRCTN12099530, identifier ISRCTN12099530.

Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure Susceptibility.

Maintaining average activity within a set-point range constitutes a fundamental property of central neural circuits. However, whether and how activity set points are regulated remains unknown. Integrating genome-scale metabolic modeling and experimental study of neuronal homeostasis, we identified mitochondrial dihydroorotate dehydrogenase (DHODH) as a regulator of activity set points in hippocampal networks. The DHODH inhibitor teriflunomide stably suppressed mean firing rates via synaptic and intrinsic excitability mechanisms by modulating mitochondrial Ca2+ buffering and spare respiratory capacity. Bi-directional activity perturbations under DHODH blockade triggered firing rate compensation, while stabilizing firing to the lower level, indicating a change in the firing rate set point. In vivo, teriflunomide decreased CA3-CA1 synaptic transmission and CA1 mean firing rate and attenuated susceptibility to seizures, even in the intractable Dravet syndrome epilepsy model. Our results uncover mitochondria as a key regulator of activity set points, demonstrate the differential regulation of set points and compensatory mechanisms, and propose a new strategy to treat epilepsy.

IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses.

The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer's disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca(2+) transients, while promoting spontaneous transmission and resting Ca(2+) level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca(2+) buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer's disease.

APP homodimers transduce an amyloid-ß-mediated increase in release probability at excitatory synapses.

Accumulation of amyloid-ß peptides (Aß), the proteolytic products of the amyloid precursor protein (APP), induces a variety of synaptic dysfunctions ranging from hyperactivity to depression that are thought to cause cognitive decline in Alzheimer's disease. While depression of synaptic transmission has been extensively studied, the mechanisms underlying synaptic hyperactivity remain unknown. Here, we show that Aß40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. Aß40 binds to the APP, increases the APP homodimer fraction at the plasma membrane, and promotes APP-APP interactions. The APP activation induces structural rearrangements in the APP/Gi/o-protein complex, boosting presynaptic calcium flux and vesicle release. The APP growth-factor-like domain (GFLD) mediates APP-APP conformational changes and presynaptic enhancement. Thus, the APP homodimer constitutes a presynaptic receptor that transduces signal from Aß40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer's disease.

Spike bursts increase amyloid-ß 40/42 ratio by inducing a presenilin-1 conformational change.

Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-ß Aß40 and Aß42 isoforms is central to familial Alzheimer's disease (FAD) pathogenesis. However, FAD mutations account for only 1-2% of Alzheimer's disease cases, leaving the experience-dependent mechanisms regulating Aß40/42 an enigma. Here we explored regulation of Aß40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted Aß40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of γ-secretase, and subsequent increase in Aß40 production. Conversely, single spikes did not alter basal PS1 conformation and Aß40/42. Burst-induced PS1 conformational shift was mediated by means of Ca(2+)-dependent synaptic vesicle exocytosis. Presynaptic inhibition in vitro and visual deprivation in vivo augmented synaptic and Aß40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating Aß40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease.