Synaptic cadherin adhesion complexes are known to be key regulators of synapse plasticity. However, the molecular mechanisms that coordinate activity-induced modifications in cadherin localization and adhesion and subsequent changes in synapse morphology and efficacy, remain unanswered. We demonstrate that the intracellular cadherin binding protein, δ-catenin, is transiently palmitoylated by DHHC5 following enhanced synaptic activity, and that palmitoylation increases δ-catenin/cadherin interactions at synapses. Both the palmitoylation of δ-catenin and its binding to cadherin are required for activity-induced stabilization of N-cadherin at synapses, the enlargement of postsynaptic spines, as well as insertion of GluA1 and GluA2 subunits into the synaptic membrane and the concomitant increase in mEPSC amplitude. Importantly, context-dependent fear conditioning in mice results in increased δ-catenin palmitoylation as well as increased δ-catenin/cadherin associations at hippocampal synapses. Together, this suggests a role for palmitoylated δ-catenin in coordinating activity-dependent changes in synaptic adhesion molecules, synapse structure, and receptor localization that are involved in memory formation.

TDP-43 is a major protein component of pathological neuronal inclusions that are present in frontotemporal dementia and amyotrophic lateral sclerosis. We report that TDP-43 plays an important role in dendritic spine formation in the cortex. The density of spines on YFP+ pyramidal neurons in both the motor and somatosensory cortex of Thy1-YFP mice, increased significantly from postnatal day 30 (P30), to peak at P60, before being pruned by P90. By comparison, dendritic spine density was significantly reduced in the motor cortex of Thy1-YFP::TDP-43A315T transgenic mice prior to symptom onset (P60), and in the motor and somatosensory cortex at symptom onset (P90). Morphological spine-type analysis revealed that there was a significant impairment in the development of basal mushroom spines in the motor cortex of Thy1-YFP::TDP-43A315T mice compared to Thy1-YFP control. Furthermore, reductions in spine density corresponded to mislocalisation of TDP-43 immunoreactivity and lowered efficacy of synaptic transmission as determined by electrophysiology at P60. We conclude that mutated TDP-43 has a significant pathological effect at the dendritic spine that is associated with attenuated neural transmission.

Highlights d Altering neuronal activity reversibly modifies node of Ranvier length d Neuronal activity alters periaxonal space width in the adult mouse brain d Nodal and periaxonal plasticities synergistically modulate action potential speed d The level of skill acquisition with learning correlates with action potential speed

The orbitofrontal cortex (OFC) integrates sensory information with the current value of foods and updates actions based on this information. Obese humans and rats fed a cafeteria diet have impaired devaluation of food rewards, implicating a potential obesity-induced dysfunction of the OFC. We hypothesized that obesity alters OFC © 2016 Macmillan Publishers Limited. All rights reserved. 3pyramidal neuronal structure and function and reduces conditioned suppression of feeding. Rats were given restricted (1 h/day), extended (23 h/day) or no (chow only) access to a cafeteria diet and tested for a conditioned suppression of feeding. Golgicox impregnation and whole-cell patch clamp experiments were performed in lateral OFC pyramidal neurons of rats from the 3 feeding groups. Rats with 40 days of extended, but not restricted, access to a cafeteria diet became obese and continued to feed during foot shock-predicting cues. Access to a cafeteria diet induced morphological changes in basilar dendrites of lateral OFC pyramidal neurons. While there were no alterations in excitatory synaptic transmission underlying altered spine density, we observed a more depolarized resting membrane potential. This was accompanied by decreased inhibitory synaptic transmission onto lateral OFC pyramidal neurons due to decreased release probability at GABAergic inputs. These changes could underlie the inability of the OFC to encode changes in the motivation value of food that is observed in obese rodents and humans.

Modulation of the concentration of dopamine (DA) released from dopaminergic terminals in the nucleus accumbens (NAc) influences behaviours such as the motivation to obtain drugs of abuse. γ-Aminobutyric acid type B (GABAB ) receptors are expressed throughout the mesolimbic circuit, including in the NAc, and baclofen, an agonist of GABAB receptors, can decrease drug-seeking behaviours. However, the mechanism by which GABAB receptors modulate terminal DA release has not been well studied. We explored how baclofen modulates the concentration of DA released from terminals in the NAc core using fast-scan cyclic voltammetry in brain slices from adult male C57BL/6J mice. We found that baclofen concentration-dependently decreased single pulse-evoked DA release. This effect was blocked by the GABAB antagonist, CGP 52432, but not by a nicotinic acetylcholine receptor antagonist. Suppression of DA release by a saturating concentration of baclofen was sustained for up to 1 h. The effect of baclofen was reduced with electrical stimulations mimicking burst firing of DA neurons. Similar to the D2 receptor agonist, quinpirole, baclofen reduced the probability of DA release, supporting a mechanistic overlap with D2 receptors. Baclofen-mediated suppression of DA release persisted after a locomotor-sensitizing cocaine treatment, indicating that GABAB receptors on DA terminals were not altered by cocaine exposure. These data suggest that baclofen-mediated suppression of terminal DA release is due to GABAB activation on DA terminals to reduce the probability of DA release. This effect does not readily desensitize, and persists regardless of chronic cocaine treatment.

Oligodendrocyte progenitor cells (OPCs) are immature cells in the central nervous system (CNS) that can rapidly respond to changes within their environment by modulating their proliferation, motility and differentiation. OPCs differentiate into myelinating oligodendrocytes throughout life, and both cell types have been implicated in maintaining and modulating neuronal function to affect motor performance, cognition and emotional state. However, questions remain about the mechanisms employed by OPCs and oligodendrocytes to regulate circuit function, including whether OPCs can only influence circuits through their generation of new oligodendrocytes, or can play other regulatory roles within the CNS. In this review, we detail the molecular and cellular mechanisms that allow OPCs, newborn oligodendrocytes and pre-existing oligodendrocytes to regulate circuit function and ultimately influence behavioral outcomes.

Obesity has reached epidemic prevalence, and much research has focused on homeostatic and nonhomeostatic mechanisms underlying overconsumption of food. Mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), is a key substrate for nonhomeostatic feeding. The goal of the present review is to compare changes in mesolimbic dopamine function in human obesity with diet-induced obesity in rodents. Additionally, we will review the literature to determine if dopamine signaling is altered with binge eating disorder in humans or binge eating modeled in rodents. Finally, we assess modulation of dopamine neurons by neuropeptides and peripheral peptidergic signals that occur with obesity or binge eating. We find that while decreased dopamine concentration is observed with obesity, there is inconsistency outside the human literature on the relationship between striatal D2 receptor expression and obesity. Finally, few studies have explored how orexigenic or anorexigenic peptides modulate dopamine neuronal activity or striatal dopamine in obese models. However, ghrelin modulation of dopamine neurons may be an important factor for driving binge feeding in rodents.

Throughout life, oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes. OPCs express cell surface receptors and channels that allow them to detect and respond to neuronal activity, including voltage‐gated calcium channel (VGCC)s. The major L‐type VGCC expressed by developmental OPCs, CaV1.2, regulates their differentiation. However, it is unclear whether CaV1.2 similarly influences OPC behavior in the healthy adult central nervous system (CNS). To examine the role of CaV1.2 in adulthood, we conditionally deleted this channel from OPCs by administering tamoxifen to P60 Cacna1c fl/fl (control) and Pdgfrα‐CreER:: Cacna1c fl/fl (CaV1.2‐deleted) mice. Whole cell patch clamp analysis revealed that CaV1.2 deletion reduced L‐type voltage‐gated calcium entry into adult OPCs by ~60%, confirming that it remains the major L‐type VGCC expressed by OPCs in adulthood. The conditional deletion of CaV1.2 from adult OPCs significantly increased their proliferation but did not affect the number of new oligodendrocytes produced or influence the length or number of internodes they elaborated. Unexpectedly, CaV1.2 deletion resulted in the dramatic loss of OPCs from the corpus callosum, such that 7 days after tamoxifen administration CaV1.2‐deleted mice had an OPC density ~42% that of control mice. OPC density recovered within 2 weeks of CaV1.2 deletion, as the lost OPCs were replaced by surviving CaV1.2‐deleted OPCs. As OPC density was not affected in the motor cortex or spinal cord, we conclude that calcium entry through CaV1.2 is a critical survival signal for a subpopulation of callosal OPCs but not for all OPCs in the mature CNS.