Understanding E-I imbalance has important implications for developing better pharmacological and behavioural treatments for ASD, including TMS, new drugs, biomarkers and patient stratification.

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.

Activation of metabotropic- (mGluRs) or NMDA-type glutamate receptors (NMDARs) are each linked to inducing long-term depression (LTD) of synaptic transmission in CA1 hippocampal neurons. These two forms of LTD are triggered by diverse signaling pathways yet both are expressed by the internalization of AMPA-type glutamate receptors (AMPARs). An unanswered question remains as to whether the convergence of the mGluR and NMDAR signaling pathways on AMPAR endocytosis renders these two forms of plasticity functionally equivalent, with both pathways inducing endocytosis of the same population of synaptic AMPARs. We now report evidence that these pathways couple to the endocytosis of distinct populations of AMPARs defined by their mobility in the membrane surface NMDAR activation enhances removal of surface. AMPARs that rapidly cycle into and out of the membrane surface, while activation of mGluRs with DHPG results in the internalization of a non-mobile population of AMPARs. Glutamate Receptor Interacting Proteins 1 and 2 (GRIP1/2) play a key role in defining the non-cycling receptor population. GRIP1/2 knockdown with siRNA increases the proportion of rapidly cycling surface AMPARs and inhibits mGluR- but not NMDAR-mediated AMPAR internalization. Additionally, we find that mGluR activation dissociates surface AMPARs from GRIP1/2 while stimulation of NMDARs elicits the loss of membrane receptors not bound to GRIP1/2. We propose that these two receptor pathways can drive the endocytosis of distinct populations of AMPARs: NMDARs couple to the endocytosis of rapidly cycling surface AMPARs not directly associated with GRIP1/2 while mGluR activation induces the endocytosis of non-cycling GRIP-bound surface AMPARs.

COVID-19 is associated with neuropsychiatric complications, the most frequent one being anxiety. Multiple biological and psychosocial factors contribute to anxiety in COVID-19. Among the biological factors, stress, genetics, gender, immune system, resilience, anosmia, hypogeusia, and central nervous system infection with SARS-CoV-2 are key. Anxiety is a complication of COVID-19 that may exacerbate the infection course, and the infection may exacerbate anxiety. We present the mechanisms of anxiety in symptomatic or asymptomatic COVID-19. We discuss the presentation of anxiety in patients without or with prior psychiatric illness, and with co-morbidities. Timely diagnosis and management of anxiety in COVID-19 patients is important. Given the frequent complication of COVID-19 with Acute Respiratory Distress Syndrome and Intensive Care Unit stay, anxiety may be a long-term complication. We review the diagnostic tools for anxiety in COVID-19, and summarise pharmacologic and non-pharmacologic treatments. We provide recommendations for diagnosis, treatment, prevention and follow up of anxiety in COVID-19. KEY POINTS Patients with COVID-19 (symptomatic or asymptomatic) exhibit a high frequency of neuropsychiatric complications with highest percentage attributed to anxiety. Multiple biological and psychosocial risk factors for anxiety exist in COVID-19-ill individuals. Biological risk factors include stress, resilience, genetics, gender, age, immune system, direct infection of the central nervous system (CNS) with SARS-CoV-2, comorbid psychiatric and general medical illnesses, ARDS and ICU stay. Anosmia and hypogeusia are COVID-19-specific anxiety risk factors. Knowledge of the anxiety risk factors is essential to focus on timely interventions, because anxiety may be a complication of and exacerbate the COVID-19 course. An inverse correlation exists between resilience and anxiety because of COVID-19, and therefore efforts should be made to increase resilience in COVID-19 patients. In COVID-19, important anxiety mechanism is neuroinflammation resulting from activation of the immune system and an ensuing cytokine storm. The general approach to management of anxiety in COVID-19 should be compassionate, similar to that during trauma or disaster, with efforts focussed on instilling a sense of hope and resilience. In selecting pharmacological treatment of anxiety, the stress response and immune system effects should be key. Medications with cardio-respiratory adverse effects should be avoided in patients with respiratory problems. Anxiety is a disorder that will require for long-term follow up at least one month after COVID-19.

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Body dysmorphic disorder is a challenging disorder that manifests as erroneously perceived flaws in one's physical appearance and repetitive behaviors in response to appearance concerns. This disorder is also frequently comorbid with other psychiatric disorders, including major depressive disorder and autism spectrum disorder. It is currently understood to arise from a combination of biological, psychological, and environmental factors. Treatment of body dysmorphic disorder typically consists of a combination of pharmacotherapy and cognitive behavioral therapy. However, not all patients respond to treatment, and BDD symptoms remain even in those who do respond. This review outlines current pharmacological and neuromodulation treatments for body dysmorphic disorder, and suggests directions for future studies of novel treatments such as augmentation with atypical antipsychotics and the use of intranasal oxytocin in cases of body dysmorphic disorder that show residual symptomatology even with tailored monotherapy. There is emerging evidence suggesting that non-invasive neurostimulatory techniques, such as repetitive transcranial magnetic stimulation, may be of value in treatment-resistant cases.

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This proof-of-concept study demonstrates the feasibility of TSO for the treatment of ASD, including a favourable safety profile, and moderate to large effect sizes for reducing repetitive behaviours and irritability. Clinicaltrials.gov: NCT01040221.