2021 Highlights from MP

In this collection we present 12 of Molecular Psychiatry's highest impact articles from 2021, selected by Editor-in-Chief Julio Licinio. This selection includes eight papers by Nobel laureates Paul Greengard, Thomas Südhof, Eric Kandel, and Andrew Schally.

Four papers from the team of the late Nobel laureate Paul Greengard, Rockefeller University, a former member of our editorial board, represent some of his last seminal contributions to neuroscience, particularly to the neurobiology of depression and antidepressant treatment response. These include the following: (1) A paper by Umschweif et al (15 Mar 2021) showed that activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants and linking selective serotonin reuptake inhibitors (SSRI) to dynamic glutamatergic changes and implicate the p11/SMARCA3/Neurensin-2 pathway in the development of more specific and efficient therapeutic strategies for neuropsychiatric disorders. (2) An article by Seo et al (7 Jul 2021) demonstrated that ependymal cells- cerebrospinal fluid (CSF) flow regulates stress-induced depression, with results that identify a new role and a key molecular determinant for ependymal cell-driven CSF flow in mood disorders and suggest a novel strategy for development of treatments for stress-associated neurological, neurodegenerative, and psychiatric disorders. This work is highlighted in a commentary by Loureiro-Campos et al. (3) Karayol et al (13 Jan 2021) studied the role of serotonin receptor 4 (5-HT4R) in the hippocampus as they modulate mood and anxiety. This study was the first to use conditional genetic targeting to demonstrate a direct role for hippocampal 5-HT4R signaling in modulating mood and anxiety. Their findings also underscore the need for cell type-based approaches to elucidate the complex action of neuromodulatory systems on distinct neural circuits. Identification of Neurensin-2 as a novel modulator of emotional behavior. (4) The research of Umschweif et al (19 Mar 2021) showed that neurensin-2 is a novel modulator of emotional behavior: upregulation of Neurensin-2 in the hippocampus either by stress, viral overexpression, or by SMARCA3 deletion, results in depressive-like behaviors; in contrast, the deletion of Neurensin-2 confers resilience to stress and induces alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor localization to synapses.

Two papers in this selection come from Nobel Laureate Thomas Südhof, a member of our Editorial Board, and his team at Stanford: (1) Seigneur et al (22 Jun 2021) dissect the pathways and mechanisms through which cerebellin-2 regulates a serotonergic dorsal raphe circuit that controls compulsive behaviors. (2) Patzke et al (30 Apr 2021) used various independent approaches to confirm that cannabinoid receptor activation acutely increases synaptic vesicle numbers by activating synapsins in human synapses.

The work of Leroy and colleagues at Columbia University, including Nobel laureate Eric Kandel, (14 May 2021) indicate that enkephalin release from vasoactive intestinal peptide (VIP)-expressing interneurons in the CA2/3a region of the hippocampus mediate heterosynaptic plasticity and social memory.

The contribution by our Editorial Board member Nobel laureate Andrew Schally, Veterans Affairs Medical Center and University of Miami, (Recinella et al, 30 Jul 2021) showed that in adult mice the growth hormone-releasing hormone (GHRH) receptor antagonist MIA-602 exhibits anti-inflammatory and antioxidant effects in ex vivo and in vivo experimental models, inducing anxiolytic and antidepressant-like behavior in mice subcutaneously treated for 4 weeks. They suggest that GHRH analogs could be tried clinically for the treatment of mood disorders including post-traumatic stress disorder (PTSD).

Pasko Rakic, Yale University, whose work showed how neurons migrate into position in the developing brain, is among the world’s top scientists: “I consider Pasko to be one of the most brilliant neuroscientists not just of this generation but in the history of neuroscience,” says Susan Hockfield, former provost of Yale and now president of the Massachusetts Institute of Technology. “What he's contributed to neuroscience is really on the order of Cajal or Golgi.” Duque, Arellano & Rakic (19 Oct 2021) provide a critical assessment of the existence of adult neurogenesis in humans and value of its rodent models for neuropsychiatric diseases. They argue that reports that neglect significant structural and functional species-specific differences have the potential to mislead the general population into believing that there might be a cure for a variety of neuropsychiatric diseases as well as stroke and brain trauma by genesis of new neurons and their incorporation into existing synaptic circuitry.

Kim Do and Michel Cuenod, Lausanne University Hospital (10 Nov 2021), provide an elegant and compelling overview of a growing body of evidence, including their own pioneering and groundbreaking work, demonstrating a pathological link between oxidative stress and schizophrenia. This evidence identifies oxidative stress as a convergence point or “central hub” for schizophrenia genetic and environmental risk factors. They review the existing experimental and translational research pinpointing the complex dynamics of oxidative stress mechanisms and their modulation in relation to schizophrenia pathophysiology.

Jose Menchon et al, University of Barcelona (29 Oct 2021), present the exciting results of a prospective, open-label, international multi-center interventional study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder.

Of course, given the fact that we are in the middle of a major worldwide pandemic caused by SARS-CoV-2, our 12th highlighted paper by Nicolas Hoertel et al, Corentin-Celton Hospital, INSERM Institute of Psychiatry and Neuroscience of Paris, and University of Paris (04 Feb 2021), describes results from an observational study demonstrating an association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19.

2021 Highlights