Astroglia have recently been implicated in various functions in the brain including modulating neuronal network functions, forming components of the blood brain barrier, and responding to neuroinflammation. Indeed, the neocortex contains neuronal circuits responsible for mediating complex higher-order behaviours and astroglia have recently been implicated in modulating neocortical behaviours. Neocortical astroglia express gonadal hormone receptors and respond to alterations in circulating gonadal hormones, which readily access the brain, with changes in function as well as protein and gene expression. In female rodents, circulating levels of estrogen and progesterone fluctuate across the estrous cycle and these cyclic changes might be expected to alter astroglia function. While some work has characterized astroglial protein expression changes during the estrous cycle in the cortex, no one has examined changes in active gene translation in astroglia across the estrous cycle. We use translating ribosome affinity purification with RNA sequencing (TRAPseq) to characterize the astroglial translatome in adult female mice during metestrus, proestrus, and estrus and compared it with that of male mice. We find the largest differences in the translatome between proestrus and estrus, and that males and females on metestrus cluster closely together, suggesting the neocortical astroglial translatome is responsive to circulating gonadal hormones. Additionally, neuroplastic processes are amongst the top gene ontologies called when examining differentially expressed genes between the different days of the cycle and between the days of the cycle. This suggests that cortical astrocyte phenotypes are rapidly modified across the estrous cycle, which may influence neocortical neuronal network function.

Esketamine has emerged as a fast-acting antidepressant option for individuals with treatment-resistant depression (TRD). Yet, little is known about how sex-assigned-at-birth shapes symptom-specific responses to these interventions, a critical gap in the move toward precision psychiatry. To address this gap, we conducted a pooled analysis of five randomized, double-blind, placebo-controlled trials in which adults with TRD received intranasal esketamine or placebo twice weekly for four weeks, alongside a newly initiated oral antidepressant. We evaluated the effects of sex-assigned-at-birth on overall depression severity, measured via total Montgomery-Åsberg Depression Rating Scale (MADRS) scores, across four symptom factors: sadness, negative thoughts, detachment, and neurovegetative symptoms, and rates of clinical response and remission. Esketamine treatment improved total MADRS scores in both sexes. However, females showed greater improvement in total MADRS scores and higher odds of treatment-response than males towards the end of the trials, in both the placebo and esketamine arms. Females also showed more pronounced reductions in the sadness and detachment factors at the end of the trials, as well as in the neurovegetative factor on day 15, regardless of treatment group. On the other hand, males showed a significant reduction in sadness symptoms after esketamine on day 2. These findings reveal that sex-assigned-at-birth influences overall antidepressant response and shapes the trajectory and symptom profile of improvement. Our findings emphasize the importance of incorporating sex-assigned-at-birth as a key variable to consider for optimizing TRD treatment strategies and advancing precision mental care.

Repetitive mild head injuries incurred while playing organized sports, during car accidents and falls, or in active military service are a major health problem. These head injuries induce cognitive, motor, and behavioral deficits that can last for months and even years, with an increased risk of dementia, Parkinson’s disease, and chronic traumatic encephalopathy. There is no approved medical treatment for these types of head injuries. To this end, we tested the therapeutic effects of the naturally occurring psychedelic psilocybin, as it is known to reduce neuroinflammation and enhance neuroplasticity. Using a model of mild repetitive head injury in adult female rats, we provide data indicating that psilocybin can reduce vasogenic edema, restore normal vascular reactivity and alter resting-state functional connectivity, reduce phosphorylated tau buildup, enhance levels of brain-derived neurotrophic factor and its receptor TrkB, and modulate lipid signaling molecules. Psilocybin treatment in an adult rat model of mild repetitive head injury can reduce vasogenic edema, restore normal vascular reactivity and alter resting-state functional connectivity, reduce phosphorylated tau buildup, enhance levels of BDNF and TrkB, and modulate lipid signaling molecules.

Racemic ketamine and its enantiomer, esketamine, have emerged as fast-acting antidepressant options for individuals with treatment-resistant depression (TRD). Yet, despite growing clinical use, little is known about how sex assigned at birth shapes symptom-specific responses to these interventions, a critical gap in the move toward personalized psychiatry. We conducted a pooled analysis of five randomized, double-blind, placebo-controlled trials in which adults with TRD received intranasal esketamine or placebo twice weekly for four weeks, alongside a newly initiated oral antidepressant. We evaluated the effects of sex assigned at birth on overall depression severity, measured via total Montgomery–Åsberg Depression Rating Scale (MADRS) scores, and across four symptom factors: sadness, negative thoughts, detachment, and neurovegetative symptoms. Rates of clinical response and remission were also analyzed by sex assigned at birth. Overall, esketamine treatment improved total MADRS scores in both sexes; however, significant sex-specific patterns emerged. Females showed greater improvement in total MADRS scores than males towards the end of the trials, in both the placebo and esketamine arms. Females also showed more pronounced reductions in the sadness and detachment factors at the end of the trials, as well as in the neurovegetative factor on day 15, regardless of the treatment group. On the other hand, males showed a significant reduction in sadness symptoms after esketamine on day 2 of the treatment. Females had higher odds of responding, regardless of treatment arm, during later time points. These findings reveal that sex assigned at birth influences overall antidepressant response and shapes the trajectory and symptom profile of improvement. Our findings emphasize the critical importance of incorporating sex assigned at birth as a key variable, essential for optimizing TRD treatment strategies and advancing individualized mental healthcare. Canadian Institutes for Health Research.

Alzheimer's disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Moreover, genetic reduction of 4E-BP2 rescued memory deficits in aged APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Our findings demonstrate that strategies targeting repressors of mRNA translation correct hippocampal protein synthesis and memory deficits in AD models. Results suggest that modulating pathways controlling brain mRNA translation may confer memory benefits in AD.

Neural development is a highly intricate process that relies on the precise regulation of gene expression. While a significant focus has been placed on understanding the transcriptional control of brain development, the regulation of mRNA translation plays a fundamental role in controlling gene expression. mRNA translation in subcellular compartments distant from the cell body, such as neuronal growth cones and astrocytic processes, allows for a rapid response to the local environment. Thus, the regulation of mRNA translation influences neurodevelopmental mechanisms such as cell fate decisions, neural stem cell proliferation and differentiation, and axon guidance. As such, the dysregulation of mRNA translation can have profound consequences for neural development, leading to conditions like microcephaly, cortical malformations, autism spectrum disorders, and fragile X syndrome. This review provides an overview of mRNA translation mechanisms that control prenatal brain development and identifies significant knowledge gaps. Specifically, we focus on mRNA translation regulation through signaling cascades such as the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), the integrated stress response, Fragile X Messenger Ribonucleoprotein 1 (FMRP) and eukaryotic elongation factor 2/kinase (eEF2/eEF2K), all of which are critical for mRNA translational regulation and have been previously studied regarding brain development.

The limitations of current symptom-focused treatments drive the urgent need for effective therapies for autism and Fragile X syndrome (FXS). Currently, no approved pharmacological interventions target the core symptoms of these disorders. Advances in understanding the underlying biology of autism and FXS make this an important time to explore novel options. Indeed, several treatments have recently been tested in clinical trials, with promising results in treating core symptoms of autism and FXS. We focus on emerging interventions, such as gut microbiome therapies, anti-inflammatory approaches, bumetanide, phosphodiesterase 4D inhibitors, and endocannabinoid modulators. We also discuss factors, such as disorder heterogeneity, which may have contributed to poor efficacy in previously failed late-phase trials and impact recent trials, emphasizing the need for personalized treatment approaches.

Hippocampal mRNA translation (i.e., protein synthesis) is crucial for synaptic plasticity and memory consolidation, and becomes defective in AD. We investigated here whether the ketamine metabolite HNK could rescue transcription profiles related to mRNA translation in aged APP/PS1 mice. Mice were treated with HNK (0.5 mg/kg, i.p.) or saline daily for 14 days, and hippocampal transcriptomic changes were assessed by RNA-seq. These data were then analyzed by gene ontology (GO) enrichment and reactome analysis. GO analyses revealed significantly upregulated pathways in APP/PS1 mice (compared to WT mice) that were corrected by HNK treatment. These included regulation of programmed cell death and response to hormones and stress. Reactome pathway analyses further implicated the innate immune system and, notably, three pathways associated with RNA metabolism and translation that were aberrantly regulated in APP/PS1 mice and were rescued by HNK. Altogether, these results indicate that HNK rescues transcriptional programs associated with inflammation, impaired proteostasis, calcium signaling, and synaptic proteins in aged APP/S1 mice.

Hypoxia-ischemia (HI) is a common perinatal complication that can result in life-long morbidities and disability. The glial environment is crucial to HI prognostic outcome as each glial cell type plays a role in HI injury and impacts clinical outcomes such as autism spectrum disorder, attention-deficit/hyperactivity disorder, cerebral palsy, epilepsy, and mood disorders. Glial cells interact in a dynamic way, both with one another and with neurons to affect synaptic plasticity, inflammation, myelination, white matter injury, oligodendrocyte progenitor cell (OPC) maturation, and blood-brain-barrier (BBB) permeability. Moreover, developmental programs such as angiogenesis, myelination, and glial cell type maturation are particularly relevant for HI due to the developmental timing of the injury. To fully understand the neurobiological mechanisms that underpin HI etiology and identify novel therapeutics, glial contributions and glial systems interactions at the BBB and white matter after HI injury must be examined, while considering their respective developmental programs and adult ischemic comparisons where applicable.

Major depressive disorder (MDD) is a complex and debilitating condition affecting approximately 280 million people worldwide. Its heterogeneous nature makes it difficult to establish clinical treatment guidelines that address individual differences in treatment response. As a result, many individuals experience treatment-resistant depression (TRD) failing to respond to first-line antidepressants. This increases the burden on healthcare systems and highlights the need for new, fast-acting therapies. Psychedelics have emerged as promising candidates due to their rapid and sustained antidepressant effects, with compounds such as psilocybin demonstrating the ability to enhance neuroplasticity through 5-HT2A receptor activation. However, their hallucinogenic properties limit clinical accessibility, necessitating intensive therapeutic supervision. Non-hallucinogenic analogs, like 2-bromo-lysergic acid diethylamide (2-Br-LSD), offer a potentially safer alternative by promoting neuroplasticity without causing hallucinations. Indeed, it still remains unclear whether hallucinatory activity is required for therapeutic benefit. This thesis examines the antidepressant effects of psilocybin and 2-Br-LSD in rodent models of depression following chronic stress. It is hypothesized that both compounds will reduce depression-like behaviours in mice by modulating neural circuits involved in mood regulation. By investigating whether the therapeutic benefits can occur without hallucinations, this work aims to assess the potential of 2-Br-LSD as a more accessible treatment option for TRD.

Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022). mTOR complex 1 (mTORC1) inhibits the translation repressors, eukaryotic translation Initiation Factor 4E (eIF4E)-Binding Proteins (4E-BPs), via phosphorylation, which causes their release from eIF4E to promote mRNA translation (Hay and Sonenberg, 2004). mTORC1 promotes mitochondrial biogenesis via inhibition of 4E-BPs, by preferentially stimulating the translation of mitochondria-related mRNAs (Gandin et al., 2016; Morita et al., 2013). We investigated the mechanisms at the intersection of 4E-BP-dependent translational regulation and metabolism in microglial response to soluble Aβ. We carried out immunoblot analysis to investigate the phosphorylation status of 4E-BP1, the isoform most abundant in microglia, following exposure to Ab. We manipulated the mTOR pathway by knocking out the downstream effectors, 4E-BPs, to alleviate translation suppression in microglia in vitro and in vivo . We crossed the microglia-specific 4E-BPs knockout mouse with a RiboTag mouse to pull-down ribosome-bound mRNAs, providing a genome-wide pool of actively translating mRNAs in the absence or presence of 4E-BPs. Finally, we examined the relationship between 4E-BP1 levels and neuroinflammation markers in cerebrospinal fluid (CSF) of AD patients. We showed that 4E-BP1 is inhibited acutely upon exposure to soluble Ab, which is dependent on Spleen Tyrosine Kinase (SYK) activation upstream of mTORC1, but is reduced upon chronic exposure. Furthermore, 4E-BP1 expression is induced during prolonged exposure to Ab. The deletion of 4E-BPs in microglia in vitro leads to an increase in mitochondrial mass and reliance on oxidative phosphorylation while decreasing expression of pro-inflammatory mediators and cell death upon exposure to Ab. We observed that increased levels of 4E-BP1 in the CSF of patients with Aβ pathology are associated with higher neurodegeneration (Nfl) in the presence of microglial activation. We demonstrate that mTORC1 signaling critically impacts microglia physiology and promotes neuroprotective functions via 4E-BP1 inhibition. 4E-BP1 activity in microglia engenders a dysfunctional or detrimental state that may lead to increased neurodegeneration. Therefore, 4E-BP1 is an attractive target for microglia modulation in AD.

The synaptic plasticity in hippocampal pyramidal neurons is expressed without a need for activation of gene transcription and protein synthesis during the first hour of induction. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) regulates gene expression at the mRNA translation level and is required for the development of several forms of long-lasting hippocampal synaptic plasticity. However, it is unknown whether this temporal pattern is also present in other cell types, such as interneurons. We stimulated the Oriens-Alveus border to induce synaptic potentiation (SP) in somatostatin-expressing interneurons (SOM-INs). Pre-incubating slices with rapamycin prevented the development of SP during 40 min post-stimulation. To determine the specific role of mTORC1 in SOM-INs, we used a conditional SOM-Raptor-/- (cKO) mouse line and found that early SP did not develop in SOM-Raptor cKO mice. Moreover, we used Fmr1-/y mice, an animal model of Fragile X syndrome in which dysregulation of mTOR-dependent signaling pathway is a hallmark of its pathophysiology. Interestingly, SP did not develop in SOM-INs of Fmr1-/y mice either. We also found a reduction of excitatory synaptic currents in these interneurons in Fmr1-/y mice, while their membrane intrinsic excitability is comparable to that of wild-type mice. Taken together, we found that the earliest minutes of developing synaptic plasticity in SOM-INs are mTORC1-dependent. Furthermore, we found that this synaptic plasticity is lost in SOM-INs in Fmr1-/y mice. In sum, the definition of early-phase synaptic plasticity based on its dependency on mTORC1 and its impact on autism pathophysiology should be considered in a synapse-type-specific manner.

Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl-d-aspartic acid receptor (NMDAR), κ and μ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine.

In Alzheimer’s Disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway is essential for microglia neuroprotective roles, but it is unclear which mTOR effectors promote these neuroprotective functions. The mTOR complex 1 (mTORC1) inactivates the translation suppressors eukaryotic translation Initiation Factor 4E (eIF4E)-Binding Proteins (4E-BP) to promote mRNA translation. We show that 4E-BP1 inactivation is impaired in microglia under AD-relevant conditions. Depleting 4E-BPs in microglia increases mitochondrial metabolism, suppresses the pro-inflammatory profile, and mitigates amyloid-induced apoptosis. Furthermore, in the cerebrospinal fluid of patients with amyloid pathology, there was a positive association between microglia activation and neurodegeneration, which increases along 4E-BP1 levels. Thus, we propose the engagement mTORC1-4E-BP1 axis as a neuroprotective mechanism and a therapeutic target or biomarker for microglia modulation in AD. ### Competing Interest Statement OH has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. AAV has received research support from BetterLife Pharma and Gilgamesh Pharma, and he has received consultancy fees from L.E.K. Consulting.

The excitatory neurotransmitter glutamate plays a critical role inexperience-dependent neuroplasticity, including addiction-related processes. Todate, however, it is not possible to measure glutamate release in the livinghuman brain. Positron emission tomography (PET) with [11C]ABP688, aselective allosteric antagonist of metabotropic type 5 glutamate (mGlu5)receptors, could offer an effective strategy. To test this proposition, weconducted a series of studies in rats using microdialysis and[11C]ABP688 microPET imaging, and in humans using PET and magneticresonance spectroscopy (MRS). Significant calcium-dependent glutamate releasewas identified in the ventral striatum of awake rats (190.5 ± 34.7%,p< 0.05;n= 7) followingadministration of a low dose of ethanol (EtOH; 20%, 0.5 g/kg), a pharmacologicalchallenge readily translatable to human research. Simultaneous microdialysis andmicroPET studies in anesthetized rats yielded concurrent increases in glutamaterelease (126.9 ± 5.3%,p < 0.001;n= 11) and decreases in striatal[11C]ABP688 binding (6.8 ± 9.6%,p <0.05). These latter two effects, however, were not significantlycorrelated (r= 0.25,p= 0.46).In humans, a laboratory stressor yielded significant changes in self-reportedmood (ps < 0.041), sympathetic system activations(ps < 0.042), and the MRS index of striatalglutamate reuptake following excitatory neurotransmission, Glx/Cr levels(p= 0.048). These effects, however, were notaccompanied by significant changes in [11C]ABP688 BPND(ps > 0.21,n= 9) orcorrelated with each other (ps > 0.074). Together, thesestudies document EtOH-induced glutamate release from neurons, EtOH-induceddecreases in [11C]ABP688 binding, and stress-induced changes inglutamate turnover, yet fail to provide evidence that the PET[11C]ABP688 method can be exploited to quantify moderate changes inglutamate release. The results underscore the need for highly controlled testingconditions during PET measures of mGlu5 receptors.