Inherited retinal degenerations (IRDs) are a leading cause of blindness. Although gene-supplementation therapies have been developed, they are only available for a small proportion of recessive IRD mutations. In contrast, genome editing using clustered-regularly interspaced short palindromic repeats (CRISPR) CRISPR-associated (Cas) systems could provide alternative therapeutic avenues for treating a wide range of genetic retinal diseases through targeted knockdown or correction of mutant alleles. Progress in this rapidly evolving field has been highlighted by recent Food and Drug Administration clinical trial approval for EDIT-101 (Editas Medicine, Inc., Cambridge, MA), which has demonstrated efficacious genome editing in a mouse model of CEP290 -associated Leber congenital amaurosis and safety in nonhuman primates. Nonetheless, there remains a significant number of challenges to developing clinically viable retinal genome-editing therapies. In particular, IRD-causing mutations occur in more than 200 known genes, with considerable heterogeneity in mutation type and position within each gene. Additionally, there are remaining safety concerns over long-term expression of Cas9 in vivo . This review highlights (i) the technological advances in gene-editing technology, (ii) major safety concerns associated with retinal genome editing, and (iii) potential strategies for overcoming these challenges to develop clinical therapies.

Memories are not formed in isolation. They are associated and organized into relational knowledge structures that allow coherent thought. Failure to express such coherent thought is a key hallmark of Schizophrenia. Here we explore the hypothesis that thought disorder arises from disorganized Hippocampal cognitive maps. In doing so, we combine insights from two key lines of investigation, one concerning the neural signatures of cognitive mapping, and another that seeks to understand lower-level cellular mechanisms of cognition within a dynamical systems framework. Specifically, we propose that multiple distinct pathological pathways converge on the shallowing of Hippocampal attractors, giving rise to disorganized Hippocampal cognitive maps and driving conceptual disorganization. We discuss the available evidence at the computational, behavioural, network, and cellular levels. We also outline testable predictions from this framework, including how it could unify major chemical and psychological theories of schizophrenia and how it can provide a rationale for understanding the aetiology and treatment of the disease.

Memories are not formed in isolation. They are associated and organized into relational knowledge structures that allow coherent thought. Failure to express such coherent thought is a key hallmark of Schizophrenia. Here we explore the hypothesis that thought disorder arises from disorganized Hippocampal cognitive maps. In doing so, we combine insights from two key lines of investigation, one concerning the neural signatures of cognitive mapping, and another that seeks to understand lower-level cellular mechanisms of cognition within a dynamical systems framework. Specifically, we propose that multiple distinct pathological pathways converge on the shallowing of Hippocampal attractors, giving rise to disorganized Hippocampal cognitive maps and driving thought disorder. We discuss the available evidence at the computational, behavioural, network and cellular levels. We also outline testable predictions from this framework including how it could unify major chemical and psychological theories of schizophrenia and how it can provide a rationale for understanding the aetiology and treatment of the disease.

Responding to the so called “inflammatory soup” has often been regarded as the sole domain of sensory afferent neurons. We tested the hypothesis that efferent sympathetic neurons can also directly respond to traditionally afferent stimuli. We used single cell RNA‐sequencing (scRNAseq) to explore transcript expression of membrane G protein and ion channel coupled receptors in the sympathetic neuronal population within the stellate ganglia of 5–6‐week‐old Wistar rats. Agonist responses were then evaluated using Fura‐2 AM calcium imaging and perforated patch clamp recordings in isolated cultured neurons. ScRNAseq identified transcript expression of transient receptor potential (TRP) channels (TRPV2>TRM7>TRPC1>>TRM4). Certain TRP channel activators (10 mM camphor n=18, 10 mM cannabidiol n=16, and 100 mM 2‐APB n=15) caused large baseline calcium influxes, which were blocked by the TRP channel inhibitor ruthenium red (RuR, 10 mM; Camphor n=7; Cannabidiol n=24; 2‐APB n=11). An accompanying depolarization of the resting membrane potential and spontaneous firing was also observed, which was reduced by RuR. Other TRP channel activators (100 mM menthol n=15, 1 mM capsaicin n=16, 500 mM AITC n=9, 1 mM vanillin n=15, 300 nM JT010 n=15, 100 mM cavracol n=13, 10 mM icillin n=10, 50 mM naltriben n=15, pH=6.5 n=16 and 100 ng/ml IGF‐1 n=12) failed to produce significant responses. ScRNAseq also identified transcript expression of receptors for inflammatory mediators, for example histamine (HRH3) and prostaglandin E2 (PTGER2 and PTGER3). Stimulation of these receptors (100 mM histamine n=11 and 1 mM prostaglandin E2 n=8) had no effect on baseline [Ca2+]I, but were able to reduce Ca2+ influx in response to KCl depolarization (50 mM) or nicotine (100 mM). Overall, these data are important when interpreting stellate ganglia sympathetic neurons as purely efferent, with evidence that neuronal excitability can be directly influenced by sensory signaling pathways. Support or Funding Information This project was supported by the Wellcome trust and the British Heart Foundation