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On the anniversary of the Boyden et al. (2005) paper that introduced the use of channelrhodopsin in neurons, Nature Neuroscience asks selected members of the community to comment on the utility, impact and future of this important technique.

Cannabinoid signalling is a major regulator of neurotransmitter release and plasticity at both excitatory and inhibitory synapses. In this Review, Soltesz and colleagues discuss emerging principles of cannabinoid control of network oscillations and their relevance for epilepsy and related comorbidities.

The study of neural plasticity has focused on excitatory neural connections, but inhibitory connections can also change. Learning at inhibitory synapses may support high-level cognitive phenomena, such as selecting information for memory storage.

The posterior hippocampal tail is an important seizure node in humans and may be a promising interventional target in epilepsy.

Current treatment options are, for many patients with epilepsy, either insufficient or ineffective and, thus, new therapeutic methodologies are necessary. In this Perspective, Esther Krook-Magnuson and Ivan Soltesz look at recent advances in optogenetic-based modulation of circuit activity and seizures with an eye toward the prospect - and challenges - of utilizing these technologies for the treatment of epilepsy.

Temporal lobe epilepsy in adults does not always respond to treatment. Krook-Magnuson and colleagues use optogenetics to inhibit and activate excitatory and inhibitory neurons, respectively, in a mouse model of temporal lobe epilepsy, and find that they can stop seizures on a moment-to-moment basis.

Modular synthetic G-protein-coupled receptors with nanobody-based ligand-recognition domains can be designed and used to programme transgene expression, real-time fluorescence or endogenous G-protein activation in response to soluble or cell-surface ligands, enabling control of diverse cellular behaviours.

Földy et al. find that GABA_A receptor–mediated synaptic inputs from murine parvalbumin-expressing basket cells are selectively modulated by the membrane voltage– and intracellular chloride–dependent chloride channel ClC-2. Their data reveal a cell type–specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons.

This study shows that cannabinoid-1 receptor (CB1)-positive inhibitory interneurons in the entorhinal cortex selectively innervate those principal neurons that project to the hippocampal commissure. Principal neurons that form the perforant path from entorhinal cortex to hippocampal dentate gyrus were devoid of CB1-positive synapses.

The hippocampal dentate spike, an understudied population event that frequently occurs between sharp-wave ripples, may underlie a mechanism re-engaging the brain with the external world during synchronous population events, and support memory during non-locomotor behaviour.

A genetically encoded sensor reveals the dynamics of endocannabinoid signaling.

Traditional systematic anti-seizure treatments alter brain-wide activity and often carry significant side effects. The authors engineered an inhibitory, acetylcholine receptor-based, chemogenetic tool to suppress targeted neurons, enabling control of chronic seizures in mice.

Discrimination of neutral from harmful environments is important for survival. But how do salient contextual signals yield persisting memories? A study uncovers a circuit that increases the specificity of hippocampus-based memories.

Combining patch-clamp recordings and subsequent STORM imaging of individual cells, the authors show that the axon terminals of perisomatically- and dendritically-projecting GABAergic interneurons show differences in CB₁ receptor number, active zone complexity, and receptor:effector ratio. Chronic exposure to THC evoked a dose-dependent and long-lasting downregulation of CB₁ at these synapses.

Investigations of a neurotransmitter receptor required for 'background' neuronal inhibition in mice show the importance of such inhibition in keeping neuronal excitability under control.

While the contribution of sharp wave ripples in memory consolidation and decision-making is established in rodent models, our understanding of their role in human memory is incomplete. Here, the authors discuss common methodological challenges in detecting, analyzing, and reporting sharp wave ripples, then they suggest practical solutions to distinguish them from other high-frequency events

Exogenous cannabinoid receptor agonists impair hippocampus-dependent learning and decrease the power of hippocampal electroencephalographic activity. A new paper shows that cannabinoids desynchronize neuronal assemblies without affecting average firing rates, and that this effect correlates with memory deficits in individuals.

Optogenetic control of neural activity in the deep brain is achieved without intracranial surgery using ChRmine.

Results are presented from the first Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment, a community-based blind test to determine the state of the art in predicting intrinsically disordered regions in proteins.

In this Review the authors discuss recent findings supporting a framework in which the hippocampus comprises principal cell subpopulations forming nonuniform parallel circuits that are independently controlled and affect a variety of behaviors.