Synaptic pathology: A shared mechanism in neurological disease. Henstridge Christopher M,Pickett Eleanor,Spires-Jones Tara L Ageing research reviews Synaptic proteomes have evolved a rich and complex diversity to allow the exquisite control of neuronal communication and information transfer. It is therefore not surprising that many neurological disorders are associated with alterations in synaptic function. As technology has advanced, our ability to study the anatomical and physiological function of synapses in greater detail has revealed a critical role for both central and peripheral synapses in neurodegenerative disease. Synapse loss has a devastating effect on cellular communication, leading to wide ranging effects such as network disruption within central neural systems and muscle wastage in the periphery. These devastating effects link synaptic pathology to a diverse range of neurological disorders, spanning Alzheimer's disease to multiple sclerosis. This review will highlight some of the current literature on synaptic integrity in animal models of disease and human post-mortem studies. Synaptic changes in normal brain ageing will also be discussed and finally the current and prospective treatments for neurodegenerative disorders will be summarised. 10.1016/j.arr.2016.04.005

Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects. Ibi Daisuke,de la Fuente Revenga Mario,Kezunovic Nebojsa,Muguruza Carolina,Saunders Justin M,Gaitonde Supriya A,Moreno José L,Ijaz Maryum K,Santosh Vishaka,Kozlenkov Alexey,Holloway Terrell,Seto Jeremy,García-Bea Aintzane,Kurita Mitsumasa,Mosley Grace E,Jiang Yan,Christoffel Daniel J,Callado Luis F,Russo Scott J,Dracheva Stella,López-Giménez Juan F,Ge Yongchao,Escalante Carlos R,Meana J Javier,Akbarian Schahram,Huntley George W,González-Maeso Javier Nature neuroscience Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment. 10.1038/nn.4616

CX3CR1 monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-α. Garré Juan Mauricio,Silva Hernandez Moura,Lafaille Juan J,Yang Guang Nature medicine Impaired learning and cognitive function often occurs during systemic infection or inflammation. Although activation of the innate immune system has been linked to the behavioral and cognitive effects that are associated with infection, the underlying mechanisms remain poorly understood. Here we mimicked viral immune activation with poly(I:C), a synthetic analog of double-stranded RNA, and longitudinally imaged postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex using two-photon microscopy. We found that peripheral immune activation caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in multiple learning tasks in mice. These observed synaptic alterations in the cortex were mediated by peripheral-monocyte-derived cells and did not require microglial function in the central nervous system. Furthermore, activation of CX3CR1Ly6C monocytes impaired motor learning and learning-related dendritic spine plasticity through tumor necrosis factor (TNF)-α-dependent mechanisms. Taken together, our results highlight CX3CR1 monocytes and TNF-α as potential therapeutic targets for preventing infection-induced cognitive dysfunction. 10.1038/nm.4340

Rapid Cortical Plasticity Supports Long-Term Memory Formation. Hebscher Melissa,Wing Erik,Ryan Jennifer,Gilboa Asaf Trends in cognitive sciences The standard systems consolidation account posits that recently formed memories are initially dependent on the hippocampus and only gradually become instantiated in neocortical networks over a period of weeks to years. However, recent animal and human research has identified rapid formation of cortical engrams at the time of learning that can support hippocampal-independent memories within hours or days. Conditions that promote rapid cortical learning include relatedness to prior knowledge, activation of knowledge in the service of action selection or active discovery, and repeated retrieval. Here, we propose that cortical hubs can support rapid learning through synchronous activation of sensorimotor representational cortices. Candidate neurobiological mechanisms include unmasking of latent synaptic connections and rapid synaptic remodeling driven by disinhibitory processes. 10.1016/j.tics.2019.09.009