CRMP2 conditional knockout changes axonal function and ultrastructure of axons in mice corpus callosum.

Collapsin response mediator protein 2 (CRMP2) is a member of a protein family, which is highly involved in neurodevelopment, but most of its members become heavily downregulated in adulthood. CRMP2 is an important factor in neuronal polarization, axonal formation and growth cone collapse. The protein remains expressed in adulthood, but is more region specific. CRMP2 is present in adult corpus callosum (CC) and in plastic areas like prefrontal cortex and hippocampus. CRMP2 has been implicated as one of the risk-genes for Schizophrenia (SZ). Here, a CRMP2 conditional knockout (CRMP2-cKO) mouse was used as a model of SZ to investigate how it could affect the white matter and therefore brain connectivity. Multielectrode electrophysiology (MEA) was used to study the function of corpus callosum showing an increase in conduction velocity (CV) measured as Compound Action Potentials (CAPs) in acute brain slices. Light- and electron-microscopy, specifically Serial Block-face Scanning Electron Microscopy (SBF-SEM), methods were used to study the structure of CC in CRMP2-cKO mice. A decrease in CC volume of CRMP2-cKO mice as compared to controls was observed. No differences were found in numbers nor in the size of CC oligodendrocytes (OLs). Similarly, no differences were found in myelin thickness or in node of Ranvier (NR) structure. In contrast, abnormally smaller axons were measured in the CRMP2-cKO mice. Using these state-of-the-art methods it was possible to shed light on specific parts of the dysconnectivity aspect of deletion of CRMP2 related to SZ and add details to previous findings helping further understanding the disease. This paper substantiates the white matter changes in the absence of CRMP2 and ties it to the role it plays in this complex disorder.

Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism.

Chronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of lPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of lPBN IL-6. These results indicate that lPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with lPBN IL-6.

A single dose of cocaine potentiates glutamatergic synaptic transmission onto locus coeruleus neurons.

The brainstem locus coeruleus (LC), the primary norepinephrinergic (NE) nucleus in the brain, has been implicated in the abuse of drugs such as opioids. However, whether and how the LC-NE system is involved in cocaine addiction remains elusive. Here, we demonstrated cocaine-evoked synaptic plasticity of glutamatergic transmission onto LC neurons as one of the earliest traces occurring after a single injection of cocaine. Twenty-four hours after mice were injected intraperitoneally with cocaine, the evoked α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated synaptic transmission onto LC neurons were strongly potentiated without major effect on N-methyl-d-aspartate receptor (NMDAR) mediated synaptic transmission. Compared with saline-pretreated mice, AMPAR-mediated excitatory postsynaptic currents (EPSCs) of cocaine-pretreated mice showed a marked inward rectification, demonstrating the insertion of GluR2-lacking AMPARs to plasma membrane. In addition, the single injection of cocaine did not affect presynaptic glutamate release probability measured by paired pulse ratio. Furthermore, we found that the cocaine-induced potentiation of AMPAR EPSCs could be blocked by prazosin, an inhibitor of α1-adrenoreceptor (AR), indicating that cocaine increases AMPAR transmission via α1-ARs. These results reveal that LC-NE serves as an initial target of drug intake.