Updated December 3, 2019
Research Spotlight
Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications
Aagaard Andersen et al. investigated the effect of chronic LRRK2 inhibition on neuronal activity in subthalamic nucleus of a Parkinson's disease model. LRRK2 is genetically linked to development of Parkinson's disease and acute and chronic modulation is previously suggested to modulate the disease. The authors found that chronic inhibition of LRRK2 in the AAV alpha-synuclein disease model did not change neuronal firing in subthalamic nucleus, which contrasts previous findings after acute LRRK2 inhibition. The findings outline the complexity of LRRK2 in development and as a treatment target in Parkinson's disease.
Dexamethasone Attenuates Hyperexcitability Provoked by Experimental Febrile Status Epilepticus
The role of neuro-inflammation in the mechanisms of epilepsy development is important because inflammatory mediators provide tractable targets for intervention. Inflammation involves numerous interacting pathways so addressing each separately has been only partially successful. Garcia-Curran et al. show in a rodent model that a sledgehammer approach using the clinically available broad antiinflammatory drug dexamethasone drastically attenuates inflammation, blood brain barrier disruption and biomarkers of epilepsy development provoked by fever-related seizures, a common antecedent of epilepsy. This post-insult intervention may be clinically translatable.
Excitatory pyramidal neurons in the primary motor cortex project bilaterally to the striatum. Whether synapses formed by ipsilateral and contralateral cortical efferents on striatal medium spiny neurons have similar or different features is unknown. This study shows that the contralateral cortico-striatal pathway has higher levels of GluN2B-containing NMDARs than the ipsilateral pathway, which contribute to different forms of LTP and LTD in these two pathways. These findings provide a novel mechanistic insight into how cortical neurons distinctly modulate ipsilateral and contralateral subcortical regions.
Also of Interest
Adolescent alcohol exposure is a serious public health problem and contributes to alcohol use and anxiety disorders later in life. In this study, we identify microRNA-137, a small non-coding RNA, in the central nucleus of amygdala (CeA) as a crucial regulator of increased alcohol consumption and anxiety-like behavior in adult rats after adolescent intermittent ethanol (AIE) exposure. Inhibition of microRNA-137 in the CeA reverses increased alcohol intake and anxiety-like behavior, and this effect is mediated by lysine-specific demethylase 1 (LSD1), a microRNA-137 target gene that regulates epigenetic programming. Thus, we have identified microRNA-137 and its target LSD1, in the CeA that play a mechanistic role in the pathogenesis of increased adult anxiety and alcohol consumption after adolescent alcohol exposure.
Differential Nicotinic Modulation of Glutamatergic and GABAergic VTA Microcircuits
This study uncovers novel aspects of nAChR neuropharmacology and VTA neurobiology that have implications for understanding nicotine dependence mechanisms. Nicotine must interact with receptors and circuits in VTA to cause dependence, and this study advances our understanding of specific nicotine-sensitive circuits that reside within this brain area. Identifying these novel nicotine-sensitive systems could provide new/additional mechanisms for targeting with smoking cessation drugs or therapeutics. Our results also add new details to the conceptual framework associated with reward circuit wiring, which could lead to an improved mechanistic understanding of natural reward processing.
Millions of people suffer from concussions every year and repeated concussions are associated with Chronic Traumatic Encephalopathy (CTE). Spreading Depolarizations (SDs) are propagating waves of brain tissue depolarization that have been associated with strokes, subarachnoid hemorrhages, and moderate to severe brain injuries. SDs have long been hypothesized to occur in mild brain injuries, but have not been recorded. Our studies are the first to directly record the electrophysiological properties of SDs following a closed skull impact, and suggest that SDs may contribute to the acute symptoms of mTBIs.
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