MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning and for the induction of Arc and BDNF.

There is considerable interest in the development of nootropics, pharmacological agents that can improve cognition across a range of both cognitive modalities and cognitive disabilities. One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur.

Arc expression regulates long-term potentiation magnitude and metaplasticity in area CA1 of the hippocampus in ArcKR mice.

Expression of the immediate early gene Arc/Arg3.1 (Arc), a key mediator of synaptic plasticity, is enhanced by neural activity and then reduced by proteasome-dependent degradation. We have previously shown that the disruption of Arc degradation, in an Arc knock-in mouse (ArcKR), where the predominant Arc ubiquitination sites were mutated, reduced the threshold to induce, and also enhanced, the strength of Group I metabotropic glutamate receptor-mediated long-term depression (DHPG-LTD).

Antagonism of P2X7 receptors enhances lorazepam action in delaying seizure onset in an in vitro model of status epilepticus.

Approximately 30% of patients with status epilepticus (SE) become refractory to two or more antiseizure medications (ASMs). There is thus a real need to identify novel targets against which to develop new ASMs for treating this clinical emergency. Among purinergic receptors, the ionotropic ATP-gated P2X7 receptor (P2X7R) has received attention as a potential ASM target.

MSK1 is required for the beneficial synaptic and cognitive effects of enriched experience across the lifespan.

Positive experiences, such as social interaction, cognitive training and physical exercise, have been shown to ameliorate some of the harms to cognition associated with ageing. Animal models of positive interventions, commonly known as environmental enrichment, strongly influence neuronal morphology and synaptic function and enhance cognitive performance. While the profound structural and functional benefits of enrichment have been appreciated for decades, little is known as to how the environment influences neurons to respond and adapt to these positive sensory experiences.

The mammalian purine salvage pathway as an exploitable route for cerebral bioenergetic support after brain injury.

Purine-based molecules play ancient, fundamental, and evolutionarily-conserved roles across life on Earth, ranging from DNA and RNA, to the universal energy currency, ATP. In mammals, the two primary routes for the synthesis of the adenine nucleotides ATP, ADP and AMP, and, as a consequence, the major bioactive metabolite adenosine, are the de novo purine biosynthesis (DNPB) pathway, and the purine salvage pathway (PSP). Of the two, the PSP dominates in both the mammalian brain and heart.

CREB serine 133 is necessary for spatial cognitive flexibility and long-term potentiation.

The transcription factor cAMP response element-binding protein (CREB) is widely regarded as orchestrating the genomic response that underpins a range of physiological functions in the central nervous system, including learning and memory. Of the means by which CREB can be regulated, emphasis has been placed on the phosphorylation of a key serine residue, S133, in the CREB protein, which is required for CREB-mediated transcriptional activation in response to a variety of activity-dependent stimuli. Understanding the role of CREB S133 has been complicated by molecular genetic techniques relying on over-expression of either dominant negative or activating transgenes that may distort the physiological role of endogenous CREB.

Selective activation of Gαob by an adenosine A receptor agonist elicits analgesia without cardiorespiratory depression.

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A receptors (ARs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists.

The glutamatergic synapse - A key hub in neuronal metabolism, signalling and plasticity.

The Special Issue of Neuropharmacology on the glutamatergic synapse is one of a series of Special Issues celebrating the 40th anniversary of Dick Evans and Jeff Watkins's seminal review on excitatory amino acids (Watkins and Evans, 1981). Through a careful appraisal of the literature extending several decades prior to the 1980s, and their own development and use of ligands for excitatory amino acid receptors, Dick and Jeff provided incontrovertible proof for the veracity and importance of glutamate as a neurotransmitter in the central nervous system. While other Special Issues in this series examine the receptors activated by glutamate (AMPA, NMDA, Kainate, mGluR and Delta/Orphan glutamate receptors) this Special Issue examines the glutamatergic synapse itself, and considers its evolution, metabolism, structure, properties and plasticity that have placed it so firmly at the centre of neuronal signalling in the central nervous system.

21st century excitatory amino acid research: A Q & A with Jeff Watkins and Dick Evans.

In 1981 Jeff Watkins and Dick Evans wrote what was to become a seminal review on excitatory amino acids (EAAs) and their receptors (Watkins and Evans, 1981). Bringing together various lines of evidence dating back over several decades on: the distribution in the nervous system of putative amino acid neurotransmitters; enzymes involved in their production and metabolism; the uptake and release of amino acids; binding of EAAs to membranes; the pharmacological action of endogenous excitatory amino acids and their synthetic analogues, and notably the actions of antagonists for the excitations caused by both nerve stimulation and exogenous agonists, often using pharmacological tools developed by Jeff and his colleagues, they provided a compelling account for EAAs, especially l-glutamate, as a bona fide neurotransmitter in the nervous system. The rest, as they say, is history, but far from being consigned to history, EAA research is in rude health well into the 21st Century as this series of Special Issues of Neuropharmacology exemplifies.

Artificial Synapse: Spatiotemporal Heterogeneities in Dopamine Electrochemistry at a Carbon Fiber Ultramicroelectrode.

An artificial synapse is developed that mimics ultramicroelectrode (UME) amperometric detection of single cell exocytosis. It comprises the nanopipette of a scanning ion conductance microscope (SICM), which delivers rapid pulses of neurotransmitter (dopamine) locally and on demand at >1000 defined locations of a carbon fiber (CF) UME in each experiment. Analysis of the resulting UME current-space-time data reveals spatiotemporal heterogeneous electrode activity on the nanoscale and submillisecond time scale for dopamine electrooxidation at typical UME detection potentials.

The influence of sensory experience on the glutamatergic synapse.

The ability of glutamatergic synaptic strength to change in response to prevailing neuronal activity is believed to underlie the capacity of animals, including humans, to learn from experience. This learning better equips animals to safely navigate challenging and potentially harmful environments, while reinforcing behaviours that are conducive to survival. Early descriptions of the influence of experience on behaviour were provided by Donald Hebb who showed that an enriched environment improved performance of rats in a variety of behavioural tasks, challenging the widely-held view at the time that psychological development and intelligence were largely predetermined through genetic inheritance.

Extract Depresses Excitatory Synaptic Transmission and Chemically-Induced Seizures in the Rat Hippocampus.

Extracts of the tropical Cinderella plant are used traditionally to manage convulsive conditions in the West African sub-region. This study sought to determine the neuronal basis of the effectiveness of these plant extracts to suppress seizure activity. Using the hippocampal slice preparation from rats, the ability of the extract to depress excitatory synaptic transmission and seizure activity were investigated.

Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor.

Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (AR) was determined in the active, G protein complexed state; this has important repercussions for structure-based drug design.

Mitogen and Stress-activated Protein Kinase 1 Negatively Regulates Hippocampal Neurogenesis.

Neurogenesis in the subgranular zone (SGZ) of the adult hippocampus can be stimulated by a variety of means, including via exposure of experimental animals to an enriched environment that provides additional sensory, social, and motor stimulation. Tangible health and cognitive benefits accrue in enriched animals, including the amelioration of signs modelling psychiatric, neurological and neurodegenerative conditions that affect humans, which may in part be due to enhanced production of neurons. A key factor in the neuronal response to enrichment is the release of brain-derived neurotrophic factor (BDNF) and the activation of the Mitogen-Activated Protein Kinase (MAPK) cascade, which can lead to the stimulation of neurogenesis.

Purines: From Diagnostic Biomarkers to Therapeutic Agents in Brain Injury.

The purines constitute a family of inter-related compounds that serve a broad range of important intracellular and extracellular biological functions. In particular, adenosine triphosphate (ATP) and its metabolite and precursor, adenosine, regulate a wide variety of cellular and systems-level physiological processes extending from ATP acting as the cellular energy currency, to the adenosine arising from the depletion of cellular ATP and responding to reduce energy demand and hence to preserve ATP during times of metabolic stress. This inter-relationship provides opportunities for both the diagnosis of energy depletion during conditions such as stroke, and the replenishment of ATP after such events.

Experience Recruits MSK1 to Expand the Dynamic Range of Synapses and Enhance Cognition.

Experience powerfully influences neuronal function and cognitive performance, but the cellular and molecular events underlying the experience-dependent enhancement of mental ability have remained elusive. In particular, the mechanisms that couple the external environment to the genomic changes underpinning this improvement are unknown. To address this, we have used male mice harboring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a brain-derived neurotrophic factor (BDNF)-activated enzyme downstream of the mitogen-activated protein kinase (MAPK) pathway.

The combination of ribose and adenine promotes adenosine release and attenuates the intensity and frequency of epileptiform activity in hippocampal slices: Evidence for the rapid depletion of cellular ATP during electrographic seizures.

In addition to being the universal cellular energy source, ATP is the primary reservoir for the neuromodulator adenosine. Consequently, adenosine is produced during ATP-depleting conditions, such as epileptic seizures, during which adenosine acts as an anticonvulsant to terminate seizure activity and raise the threshold for subsequent seizures. These actions protect neurones from excessive ionic fluxes and hence preserve the remaining cellular content of ATP.

Correction to: The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury.

The original version of Figure 4A contained superfluous text. This has now been removed.

Differential-Concentration Scanning Ion Conductance Microscopy.

Scanning ion conductance microscopy (SICM) is a nanopipette-based scanning probe microscopy technique that utilizes the ionic current flowing between an electrode inserted inside a nanopipette probe containing electrolyte solution and a second electrode placed in a bulk electrolyte bath, to provide information on a substrate of interest. For most applications to date, the composition and concentration of the electrolyte inside and outside the nanopipette is identical, but it is shown herein that it can be very beneficial to lift this restriction. In particular, an ionic concentration gradient at the end of the nanopipette, generates an ionic current with a greatly reduced electric field strength, with particular benefits for live cell imaging.

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury.

Brain slices have been the workhorse for many neuroscience labs since the pioneering work of Henry McIlwain in the 1950s. Their utility is undisputed and their acceptance as appropriate models for the central nervous system is widespread, if not universal. However, the skeleton in the closet is that ATP levels in brain slices are lower than those found in vivo, which may have important implications for cellular physiology and plasticity.

An AMPK-dependent regulatory pathway in tau-mediated toxicity.

Neurodegenerative tauopathies are characterised by accumulation of hyperphosphorylated tau aggregates primarily degraded by autophagy. The 5'AMP-activated protein kinase (AMPK) is expressed in most cells, including neurons. Alongside its metabolic functions, it is also known to be activated in Alzheimer's brains, phosphorylate tau, and be a critical autophagy activator.