Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns.

/pdf/role-of-endogenous-cannabinoids-in-synaptic-signaling-115q7g965r.pdf

Role of Endogenous Cannabinoids in Synaptic Signaling

Dendritic spines are the primary recipients of excitatory input in the central nervous system. They provide biochemical compartments that locally control the signaling mechanisms at individual synapses. Hippocampal spines show structural plasticity as the basis for the physiological changes in synaptic efficacy that underlie learning and memory. Spine structure is regulated by molecular mechanisms that are finetuned and adjusted according to developmental age, level and direction of synaptic activity, specific brain region, and exact behavioral or experimental conditions. Reciprocal changes between the structure and function of spines impact both local and global integration of signals within dendrites. Advances in imaging and computing technologies may provide the resources needed to reconstruct entire neural circuits. Key to this endeavor is having sufficient resolution to determine the extrinsic factors (such as perisynaptic astroglia) and the intrinsic factors (such as core subcellular organelles) that are required to build and maintain

/pdf/balancing-structure-and-function-at-hippocampal-dendritic-3iw7407uzm.pdf

Balancing Structure and Function at Hippocampal Dendritic Spines

During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.

https://sites.oxy.edu/clint/physio/article/TheEmergingRoleoftheEndocannabinoidSysteminEndocrineRegulationandEnergyBalance.pdf

The emerging role of the endocannabinoid system in endocrine regulation and energy balance.

The dv/dt characteristics of a bidirectional thyristor are improved by irradiating selected portions of the device with high energy crystal lattice-damaging particles. In an exemplary embodiment, the commutating dv/dt of a triac is enhanced by the masked, selective irradiation of the boundaries between conducting portions and between the gate and the conducting portions.

https://jnnp.bmj.com/content/jnnp/37/10/1182.3.full.pdf

Cerebellar cortex, cytology and organization

Increasing atmospheric carbon dioxide (CO2) concentrations are expected to decrease surface ocean pH by 0.3‐0.5 units by 2100 (refs 1,2), lowering the carbonate ion concentration of surface waters. This rapid acidification is predicted to dramatically decrease calcification in many marine organisms 3,4 . Reduced skeletal growth under increased CO2 levels has already been shown for corals, molluscs and many other marine organisms 4‐9 . The impact of acidification on the ability of individual species to calcify has remained elusive, however, as measuring net calcification fails to disentangle the relative contributions of gross calcification and dissolution rates on growth. Here, we show that corals and molluscs transplanted along gradients of carbonate saturation state at Mediterranean CO2 vents are able to calcify and grow at even faster than normal rates when exposed to the high CO2 levels projected for the next 300 years. Calcifiers remain at risk, however, owing to the dissolution of exposed shells and skeletons that occurs as pH levels fall. Our results show that tissues and external organic layers play a major role in protecting shells and skeletons from corrosive sea water, limiting dissolution and allowing organisms to calcify 10,11 . Our combined field and

/pdf/coral-and-mollusc-resistance-to-ocean-acidification-1ohgzuf00j.pdf

Coral and mollusc resistance to ocean acidification adversely affected by warming

Interactions between neuroactive steroids and reelin haploinsufficiency in Purkinje cell survival.

A principle that regulates detailed architecture in the brain is that active terminals have a competitive advantage over less active terminals in establishing synaptic connections. This principle is known to apply to fibers within a single neuronal population competing for a common target domain. Here we uncover an additional rule that applies when two neuronal populations compete for two contiguous territories. The cerebellar Purkinje cell dendrites have two different synaptic domains with spines innervated by two separate excitatory inputs, parallel fibers (PFs) and climbing fibers (CFs). Glutamate δ-2 receptors are normally present only on the PF spines where they are important for their innervation. After block of activity by tetrodotoxin, numerous new spines form in the CF domain and become innervated mainly by PFs; all spines, including those still innervated by the CFs, bear δ-2 receptors. Thus, in the absence of activity, PFs gain a competitive advantage over CFs. The entire dendritic arbor becomes a uniform territory with the molecular cues associated with the PFs. To access their proper territory and maintain synaptic contacts, CFs must be active and locally repress the cues of the competitor afferents.

Role of glutamate δ-2 receptors in activity-dependent competition between heterologous afferent fibers

Axonal competition in the synaptic wiring of the cerebellar cortex during development and in the mature cerebellum.

Two models of spine formation have been proposed. Spines can derive from emerging dendritic filopodia that have encountered presynaptic partners, or presynaptic molecules may induce the spine maturation event directly from the dendritic shaft. The first model applies better to the Purkinje cell (PC), because numerous free spines have been described in several conditions, particularly when granule cells degenerate before parallel fiber (PF) synapses are formed. A large number of new spines, many of them being free, appear in the proximal dendritic domain after blockage of electrical activity by tetrodotoxin (TTX). A complete blockage of the AMPA receptors by NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulfonamide), leading to a complete absence of PF- and climbing fiber (CF)-evoked EPSCs and of spontaneous glutamatergic quantal events, mimics the TTX effect. In contrast, metabotropic glutamate receptor blockage by MCPG [(S)-alpha-methyl-4-carboxyphenylglycine] is ineffective. In normal conditions, in the proximal dendritic domain of the PC, clusters of a few spines are present only under each CF varicosity. It has been proposed that the active CF is responsible for spine pruning in the territory surrounding the CF synapses. Here, we show that such a pruning is mediated by AMPA but not by metabotropic receptors. Finally, after AMPA receptor blockage, there is a reduced number of spines in each spine cluster underlying CF varicosity. In conclusion, PCs tend to express spines over the entire dendritic territory. CF activity reinforces the CF synaptic contacts and actively suppresses spines in the surrounding territory, which is an effect mediated by AMPA receptors.

https://www.jneurosci.org/content/jneuro/27/17/4603.full.pdf

Activity-Dependent Presynaptic and Postsynaptic Structural Plasticity in the Mature Cerebellum

A change in the pattern of activity affects the developmental regression of the Purkinje cell polyinnervation by climbing fibers in the rat cerebellum.

Roberta Cesa

Papers

Interactions between neuroactive steroids and reelin haploinsufficiency in Purkinje cell survival.

Role of glutamate δ-2 receptors in activity-dependent competition between heterologous afferent fibers

Axonal competition in the synaptic wiring of the cerebellar cortex during development and in the mature cerebellum.

Activity-Dependent Presynaptic and Postsynaptic Structural Plasticity in the Mature Cerebellum

A change in the pattern of activity affects the developmental regression of the Purkinje cell polyinnervation by climbing fibers in the rat cerebellum.