As a chemical transmitter in the mammalian central nervous system, nitric oxide (NO) is still thought a bit of an oddity, yet this role extends back to the beginnings of the evolution of the nervous system, predating many of the more familiar neurotransmitters. During the 20 years since it became known, evidence has accumulated for NO subserving an increasing number of functions in the mammalian central nervous system, as anticipated from the wide distribution of its synthetic and signal transduction machinery within it. This review attempts to probe beneath those functions and consider the cellular and molecular mechanisms through which NO evokes short- and long-term modifications in neural performance. With any transmitter, understanding its receptors is vital for decoding the language of communication. The receptor proteins specialised to detect NO are coupled to cGMP formation and provide an astonishing degree of amplification of even brief, low amplitude NO signals. Emphasis is given to the diverse ways in which NO receptor activation initiates changes in neuronal excitability and synaptic strength by acting at pre- and/or postsynaptic locations. Signalling to non-neuronal cells and an unexpected line of communication between endothelial cells and brain cells are also covered. Viewed from a mechanistic perspective, NO conforms to many of the rules governing more conventional neurotransmission, particularly of the metabotropic type, but stands out as being more economical and versatile, attributes that presumably account for its spectacular evolutionary success.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1460-9568.2008.06285.x

Concepts of neural nitric oxide‐mediated transmission

Two-pore-domain potassium (K+) channels are substrates for resting K+ currents in neurons. They are major targets for endogenous modulators, as well as for clinically important compounds such as volatile anesthetics. In the current study, we report on the CNS distribution in the rat and mouse of mRNA encoding seven two-pore-domain K+ channel family members: TASK-1 (KCNK3), TASK-2 (KCNK5), TASK-3 (KCNK9), TREK-1 (KCNK2), TREK-2 (KCNK10), TRAAK (KCNK4), and TWIK-1 (KCNK1). All of these genes were expressed in dorsal root ganglia, and for all of the genes except TASK-2, there was a differential distribution in the CNS. For TASK-1, highest mRNA accumulation was seen in the cerebellum and somatic motoneurons. TASK-3 was much more widely distributed, with robust expression in all brain regions, with particularly high expression in somatic motoneurons, cerebellar granule neurons, the locus ceruleus, and raphe nuclei and in various nuclei of the hypothalamus. TREK-1 was highest in the striatum and in parts of the cortex (layer IV) and hippocampus (CA2 pyramidal neurons). mRNA for TRAAK also was highest in the cortex, whereas expression of TREK-2 was primarily restricted to the cerebellar granule cell layer. There was widespread distribution of TWIK-1, with highest levels in the cerebellar granule cell layer, thalamic reticular nucleus, and piriform cortex. The differential expression of each of these genes likely contributes to characteristic excitability properties in distinct populations of neurons, as well as to diversity in their susceptibility to modulation.

https://www.jneurosci.org/content/jneuro/21/19/7491.full.pdf

CNS Distribution of Members of the Two-Pore-Domain (KCNK) Potassium Channel Family

TREK1 is the most extensively studied of the mammalian two-pore-forming K+channels and is widely expressed in the brain. Honore reviews the functional properties of TREK1 and describes recent results indicating its important roles in CNS function and disease. Two-pore-domain K+ (K2P) channel subunits are made up of four transmembrane segments and two pore-forming domains that are arranged in tandem and function as either homo- or heterodimeric channels. This structural motif is associated with unusual gating properties, including background channel activity and sensitivity to membrane stretch. Moreover, K2P channels are modulated by a variety of cellular lipids and pharmacological agents, including polyunsaturated fatty acids and volatile general anaesthetics. Recent in vivo studies have demonstrated that TREK1, the most thoroughly studied K2P channel, has a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain and depression.

The neuronal background K2P channels: focus on TREK1

Machine learning algorithms can be trained to estimate age from brain structural MRI. The difference between an individual’s predicted and chronological age, predicted age difference (PAD), is a phenotype of relevance to aging and brain disease. Here, we present a new deep learning approach to predict brain age from a T1-weighted MRI. The method was trained on a dataset of healthy Icelanders and tested on two datasets, IXI and UK Biobank, utilizing transfer learning to improve accuracy on new sites. A genome-wide association study (GWAS) of PAD in the UK Biobank data (discovery set: $$N=12378$$, replication set: $$N=4456$$) yielded two sequence variants, rs1452628-T ($$\beta =-0.08$$, $$P=1.15\times{10}^{-9}$$) and rs2435204-G ($$\beta =0.102$$, $$P=9.73\times 1{0}^{-12}$$). The former is near KCNK2 and correlates with reduced sulcal width, whereas the latter correlates with reduced white matter surface area and tags a well-known inversion at 17q21.31 (H2). Machine learning algorithms can be trained to estimate age from brain structural MRI. Here, the authors introduce a new deep-learning-based age prediction approach, and then carry out a GWAS of the difference between predicted and chronological age, revealing two associated variants.

/pdf/brain-age-prediction-using-deep-learning-uncovers-associated-4m47kblepx.pdf

Brain age prediction using deep learning uncovers associated sequence variants

TREK-1 is a two-pore-domain background potassium channel expressed throughout the central nervous system. It is opened by polyunsaturated fatty acids and lysophospholipids. It is inhibited by neurotransmitters that produce an increase in intracellular cAMP and by those that activate the Gq protein pathway. TREK-1 is also activated by volatile anesthetics and has been suggested to be an important target in the action of these drugs. Using mice with a disrupted TREK-1 gene, we now show that TREK-1 has an important role in neuroprotection against epilepsy and brain and spinal chord ischemia. Trek1 � /� mice display an increased sensitivity to ischemia and epilepsy. Neuroprotection by polyunsaturated fatty acids, which is impressive in Trek1 þ / þ mice, disappears in Trek1 � /� mice indicating a central role of TREK-1 in this process. Trek1 � /� mice are also resistant to anesthesia by volatile anesthetics. TREK-1 emerges as a potential innovative target for developing new therapeutic agents for neurology and anesthesiology.

TREK-1, a K þ channel involved in neuroprotection and general anesthesia

Distribution and expression of TREK-1, a two-pore-domain potassium channel, in the adult rat CNS.

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Distribution and expression of TREK-1, a two-pore-domain potassium channel, in the adult rat CNS.