In addition to cognitive impairments, neurodevelopmental disorders (NDDs) often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with NDDs are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex (SSC) weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper-lamina SSC neurons. These results were unexpected given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients.

Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (b)-adrenergic receptors (b-ARs). Previous studies demonstrated that a b-adrenergic receptor agonist, isoproterenol, can modify the threshold for long-term potentiation (LTP), a putative cellular mechanism for learning and memory, in a process known as "metaplasticity." Metaplasticity is the ability of synaptic plasticity to be modified by prior experience. We asked whether NE itself could engage metaplastic mechanisms in area CA1 of mouse hippocampal slices. Using extracellular field potential recording and stimulation, we show that application of NE (10 mM), which did not alter basal synaptic strength, enhances the future maintenance of LTP elicited by subthreshold, high-frequency stimulation (HFS: 1 × 100 Hz, 1 sec). HFS applied 30 min after NE washout induced long-lasting (.4 h) LTP, which was significantly extended in duration relative to HFS alone. This NE-induced metaplasticity required b1-AR activation, as coapplication of the b1-receptor antagonist CGP-20712A (1 mM) attenuated maintenance of LTP. We also found that NE-mediated metaplasticity was translationand transcription-dependent. Polysomal profiles of CA1 revealed increased translation rates for specific mRNAs during NEinduced metaplasticity. Thus, activation of b-ARs by NE primes synapses for future long-lasting plasticity on time scales extending beyond fast synaptic transmission; this may facilitate neural information processing and the subsequent formation of lasting memories.

Key pointsr Transcription is recruited by noradrenaline in the hippocampus. r Epigenetic mechanisms are recruited by hippocampal noradrenergic receptor activation. r Epigenetic regulation by noradrenaline offers a novel mechanism for long-term potentiation Abstract Noradrenaline (NA) is a neuromodulator that can effect long-lasting changes in synaptic strength such as long-term potentiation (LTP), a putative cellular mechanism for memory formation in the mammalian brain. Persistent LTP requires alterations in gene expression that may involve epigenetic mechanisms such as DNA methylation, histone acetylation and histone phosphorylation. It is known that β-adrenergic receptors and NA can boost LTP maintenance by regulating translation. However, it is unclear whether NA can additionally engage epigenetic mechanisms to regulate transcription and boost LTP endurance. To address this issue, we probed NA-treated mouse hippocampal slices with pharmacological inhibitors targeting epigenetic regulatory pathways and discovered that NA activates β-adrenergic receptors to boost LTP maintenance in area CA1 through DNA methylation and post-translational histone modifications. Specifically, NA paired with 100 Hz stimulation enhanced histone H3 acetylation and phosphorylation, both of which were required for NA-induced boosting of LTP maintenance. Together, our findings identify NA as a neuromodulatory transmitter capable of triggering epigenetic, transcriptional control of genes required for establishing persistent LTP in the mouse hippocampus. These modifications may contribute to the stabilization of memory.

Epigenetic mechanisms, which include DNA methylation, a variety of post-translational modifications of histone proteins (acetylation, phosphorylation, methylation, ubiquitination, sumoylation, serotonylation, dopaminylation), chromatin remodeling enzymes, and long non-coding RNAs, are robust regulators of activity-dependent changes in gene transcription. In the brain, many of these epigenetic modifications have been widely implicated in synaptic plasticity and memory formation. Dysregulation of epigenetic mechanisms has been reported in the aged brain and is associated with or contributes to memory decline across the lifespan. Furthermore, alterations in the epigenome have been reported in neurodegenerative disorders, including Alzheimer’s disease. Here, we review the diverse types of epigenetic modifications and their role in activity- and learning-dependent synaptic plasticity. We then discuss how these mechanisms become dysregulated across the lifespan and contribute to memory loss with age and in Alzheimer’s disease. Collectively, the evidence reviewed here strongly supports a role for diverse epigenetic mechanisms in memory formation, aging, and neurodegeneration in the brain.

BackgroundThe stressful academic schedule of medical students poses an obvious challenge to their daily lifestyle. Psychosomatic discomfort poses a significant risk for inaccurate self-medication for ameliorating menstrual complications and feeling better, thus directly impacting personal and academic wellbeing.ObjectiveThe impact of menstrual disturbances on academic life is not extensively explored. Therefore, the primary objective of this research was to probe the prevalence of menstrual disturbances and assess the academic and social impact. Finally, the authors provide an overview of pharmacological and other interventions students adopt to reduce clinical symptoms.MethodsA database search was conducted from the year 2016 till September 2021 for the studies reporting the prevalence of menstrual disorders in all geographic locations of the world. Keywords used for searching databases included “menstrual disturbances” and “medical students,” “prevalence” OR “symptoms” of “Premenstrual syndrome” OR “Premenstrual dysphoric disorder” OR “Dysmenorrhea” in medical students. Prospero Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) protocols were followed. The protocol was registered in the International prospective register of systematic reviews (PROSPERO), the Center for Reviews and Dissemination, University of York (CRD42021277962). The quality of the methodologies used in selected studies was evaluated by a modified version of Newcastle Ottawa Scale (NOS).ResultsInitially, 1527 articles were available. After a review, 26 papers were selected for analysis. A total of 25 citations were identified for quantitative analyses, out of which 16 studies reported Pre-menstrual syndrome, 7 reported Pre-menstrual dysphoric disorder, and 13 articles reported dysmenorrhea. The pooled prevalence of Pre-menstrual syndrome was 51.30%, Pre-menstrual dysphoric disorder was 17.7%, and dysmenorrhea was 72.70%. Most common associated lifestyle factors were stress, excessive caffeine intake and lack of exercise. Painkillers, hot packs and hot beverages were amongst the common measures taken by the students to relieve their symptoms.ConclusionsThe current situation calls for action to accommodate students' needs and bridge the social gap regarding menstrual health. Proactive measures by medical educators and stakeholders are required for an inclusive, accommodating educational environment which will minimize the gender discrepancy in academic satisfaction and professional life.