Selective Encoding of Cocaine versus Natural Rewards by Nucleus Accumbens Neurons Is Not Related to Chronic Drug Exposure

We reported previously that subsets of nucleus accumbens (Acb) neurons differentially encode information about goal-directed behaviors for "natural" (food and water) versus cocaine reward in animals well trained to self-administer the drug (Carelli et al., 2000). Here, we examined whether repeated exposure to cocaine is the crucial determinate of the selective encoding of cocaine versus water reinforcement by Acb neurons. Acb cells were recorded during a water-cocaine multiple schedule from the first day of cocaine exposure as well as during repeated sessions. Specifically, animals were initially trained to press a lever for water and were then surgically prepared for extracellular recording in the Acb. After 1 week, Acb cells were recorded during acquisition of the water-cocaine multiple schedule. Because behavioral responding for water was already established, training on the multiple schedule was divided into three components corresponding to acquisition of self-administration: (1) "initial" (day 1 of self-administration), (2) "reliable" (self-administration behavior was present but erratic), and (3) "stable" (cocaine responding was stable). During the initial component, the percentage of water-selective neurons was high compared with cocaine neurons. However, this became approximately equal with repeated self-administration experience (i.e., during the stable component). Remarkably, the percentage of neurons showing overlapping (similar) neuronal firing patterns during initial exposure to cocaine was low (<8%) and remained low during reliable and stable components. These findings support the view that separate neural circuits in the Acb differentially encode information about cocaine versus natural reward, and that this functional organization is not a direct consequence of chronic drug exposure

A Glutamate Homeostat Controls the Presynaptic Inhibition of Neurotransmitter Release

Summary: We have interrogated the synaptic dialog that enables the bi-directional, homeostatic control of presynaptic efficacy at the glutamatergic Drosophila neuromuscular junction (NMJ). We find that homeostatic depression and potentiation use disparate genetic, induction, and expression mechanisms. Specifically, homeostatic potentiation is achieved through reduced CaMKII activity postsynaptically and increased abundance of active zone material presynaptically at one of the two neuronal subtypes innervating the NMJ, while homeostatic depression occurs without alterations in CaMKII activity and is expressed at both neuronal subtypes. Furthermore, homeostatic depression is only induced through excess presynaptic glutamate release and operates with disregard to the postsynaptic response. We propose that two independent homeostats modulate presynaptic efficacy at the Drosophila NMJ: one is an intercellular signaling system that potentiates synaptic strength following diminished postsynaptic excitability, while the other adaptively modulates presynaptic glutamate release through an autocrine mechanism without feedback from the postsynaptic compartment. : Homeostatic mechanisms stabilize synaptic strength, but the signaling systems remain enigmatic. Li et al. suggest the existence of a homeostat operating at the Drosophila neuromuscular junction that responds to excess glutamate through an autocrine mechanism to adaptively inhibit presynaptic neurotransmitter release. This system parallels forms of plasticity at central synapses. Keywords: homeostatic synaptic plasticity, glutamate homeostasis, synaptic depression, Drosophila neuromuscular junctio

Correcting deregulated Fxydl expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxydl may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxydl can rescue these RTT deficits, we studied the male progeny of Fxydl null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxydl allele, suggesting that NKA activity is under Fxydl inhibitory control. Deletion of one Fxydl allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxydl failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxydl in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth. (C) 2018 Elsevier B.V. All rights reserved