Regulation of hippocampal excitatory synapses by the Zdhhc5 palmitoyl acyltransferase.

Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory, synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on the enzymatic activity of Zdhhc5, its localization at the plasma membrane and its C-terminal domain, which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

Consumption of palatable food primes food approach behavior by rapidly increasing synaptic density in the VTA.

In an environment with easy access to highly palatable and energy-dense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons.

Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors.

Astrocytes express neurotransmitter receptors that serve as sensors of synaptic activity and initiate signals leading to activity-dependent local vasodilation and increases in blood flow. We previously showed that arteriolar vasodilation produced by activation of cortical astrocytes is dependent on endothelial nitric oxide synthase (eNOS) and endogenous agonists of N-methyl-D-aspartate (NMDA) receptors. Here, we tested the hypothesis that these effects are mediated by NMDA receptors expressed by brain endothelial cells. Primary endothelial cultures expressed NMDA receptor subunits and produced nitric oxide in response to co-agonists, glutamate and D-serine. In cerebral cortex in situ, immunoelectron microscopy revealed that endothelial cells express the GluN1 NMDA receptor subunit at basolateral membrane surfaces in an orientation suitable for receiving intercellular messengers from brain cells. In cortical slices, activation of astrocytes by two-photon flash photolysis of a caged Ca2+ compound or application of a metabotropic glutamate receptor agonist caused endothelial NO generation and local vasodilation. These effects were mitigated by NMDA receptor antagonists and conditional gene silencing of endothelial GluN1, indicating at least partial dependence on endothelial NMDA receptors. Our observations identify a novel astrocyte-endothelial vasodilatory signaling axis that could contribute to endothelium-dependent vasodilation in brain functional hyperemia.

Protein palmitoylation in the development and plasticity of neuronal connections.

Protein palmitoylation, or the reversible addition of the fatty acid, palmitate, onto substrate proteins, can impact the structure and stability of proteins as well as regulate protein-protein interactions and the trafficking and localization of proteins to cell membranes. This posttranslational modification is mediated by palmitoyl-acyltransferases, consisting of a family of 23 zDHHC proteins in mammals. This review focuses on the subcellular distribution of zDHHC proteins within the neuron and the regulation of zDHHC trafficking and function by synaptic activity. We review recent studies identifying actin binding proteins, cell adhesion molecules and synaptic scaffolding proteins as targets of palmitoylation, and examine the implications of activity-mediated palmitoylation in the establishment and plasticity of neuronal connections.

Cadherins mediate cocaine-induced synaptic plasticity and behavioral conditioning.

Drugs of abuse alter synaptic connections in the reward circuitry of the brain, which leads to long-lasting behavioral changes that underlie addiction. Here we show that cadherin adhesion molecules play a critical role in mediating synaptic plasticity and behavioral changes driven by cocaine. We demonstrate that cadherin is essential for long-term potentiation in the ventral tegmental area and is recruited to the synaptic membranes of excitatory synapses onto dopaminergic neurons following cocaine-mediated behavioral conditioning. Furthermore, we show that stabilization of cadherin at the membrane of these synapses blocks cocaine-induced synaptic plasticity, leading to a reduction in conditioned place preference induced by cocaine. Our findings identify cadherins and associated molecules as targets of interest for understanding pathological plasticity associated with addiction.