Na+-sensitivity is a unique feature of Na+-activated K+ (KNa) channels, making them naturally suited to counter a sudden influx in Na+ ions. As such, it has long been suggested that KNa channels may serve a protective function against excessive excitation associated with neuronal injury and disease. This hypothesis, however, has remained largely untested. Here, we examine KNa channels encoded by the Drosophila Slo2 ( dSlo2 ) gene in males and females. We show that dSlo2/KNa channels are selectively expressed in cholinergic neurons in the adult brain, as well as in glutamatergic motor neurons, where dampening excitation may function to inhibit global hyperactivity and seizure-like behavior. Indeed, we show that effects of feeding Drosophila a cholinergic agonist are exacerbated by the loss of dSlo2/KNa channels. Similar to mammalian Slo2/KNa channels, we show that dSlo2/KNa channels encode a TTX-sensitive K+ conductance, indicating that dSlo2/KNa channels can be activated by Na+ carried by voltage-dependent...

SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A which encodes the voltage-gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of wild-type SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute dir...

Signal transmission in the brain propagates via distinct oscillatory frequency bands but the aperiodic component - 1/f activity - almost always co-exists which most of the previous studies have not sufficiently taken into consideration. We used a recently proposed parameterisation model that delimits the oscillatory and aperiodic components of neural dynamics on lifespan ageing data collected from human participants using Magnetoencephalography (MEG). Since, healthy ageing underlines an enormous change in local tissue properties, any systematic relationship of 1/f activity would highlight their impact on the self-organized critical functional states. Furthermore, we have used patterns of correlation between aperiodic background and metrics of behaviour, to understand the domain general effects of 1/f activity. We suggest that age-associated global change in 1/f baseline, alters the functional critical states of the brain affecting the global information processing impacting critically all aspects of cognit...

Detection of an unexpected, novel, or salient stimulus typically leads to an orienting response by which animals move the head, in concert with the sensors (e.g., eyes, pinna, whiskers), to evaluate the stimulus. The basal ganglia are known to control orienting movements through tonically active GABAergic neurons in the substantia nigra pars reticulata (SNr) that project to the superior colliculus. Using optogenetics, we explored the ability of GABAergic SNr neurons on one side of the brain to generate orienting movements. In a strain of mice that express channelrhodopsin (ChR2) in both SNr GABAergic neurons and afferent fibers, we found that continuous blue light produced a robust sustained excitation of SNr neurons which generated ipsiversive orienting. Conversely, in the same animal, trains of blue light excited afferent fibers more effectively than continuous blue light, producing a robust sustained inhibition of SNr neurons which generated contraversive orienting. When ChR2 expression was restricted t...

The potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes (JXP) of myelinated primary afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study we compared two mouse models of constitutive Kv1.6 knock-out achieved by different methods: traditional gene trap via homologous recombination, and CRISPR-mediated excision. Both Kv1.6 knock-out mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice ( Kcna6lacZ ) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism and we found that their central primary afferent presynaptic terminals developed a striking neurodegenerative phenotype involving accumulati...

Recent investigation of memory-related functions in the auditory system have capitalized on the use of memory-modulating molecules to probe the relationship between memory and its substrates in auditory system coding. For example, epigenetic mechanisms, which regulate gene expression necessary for memory consolidation, are powerful modulators of learning-induced neuroplasticity and long-term memory formation (LTM). Inhibition of the epigenetic regulator histone deacetylase 3 (HDAC3) promotes LTM that is highly specific for spectral features of sound. The present work demonstrates for the first time that HDAC3 inhibition also enables memory for temporal features of sound. Adult, male rats trained in an amplitude modulation (AM) rate discrimination task and treated with a selective inhibitor of HDAC3 formed memory that was highly specific to the AM rate paired with reward. Sound-specific memory revealed behaviorally was associated with a signal-specific enhancement in temporal coding in the auditory system: ...

Myelination is essential for central nervous system (CNS) formation, health and function. As a model organism, larval zebrafish have been extensively employed to investigate the molecular and cellular basis of CNS myelination, due to their genetic tractability and suitability for non-invasive live cell imaging. However, it has not been assessed to what extent CNS myelination affects neural circuit function in zebrafish larvae, prohibiting the integration of molecular and cellular analyses of myelination with concomitant network maturation. To test whether larval zebrafish might serve as a suitable platform with which to study the effects of CNS myelination and its dysregulation on circuit function, we generated zebrafish myelin regulatory factor ( myrf) mutants with CNS-specific hypomyelination and investigated how this affected their axonal conduction properties and behaviour. We found that myrf mutant larvae exhibited increased latency to perform startle responses following defined acoustic stimuli. Furt...

Cognitive impairment is a core feature of cyclin-dependent kinase-like 5 (CDKL5) deficiency, a neurodevelopmental disorder characterized by early epileptic seizures, intellectual disability, and autistic behaviors. Although loss of CDKL5 affects a number of molecular pathways, very little has been discovered about the physiological effects of these changes on the neural circuitry. We therefore studied synaptic plasticity and local circuit activity in the dentate gyrus of both Cdkl5-/y and Cdkl5+/- mutant mice. We found that CDKL5 haploinsufficiency in both male and female mice impairs hippocampus-dependent learning and memory in multiple tasks. In vivo , loss of CDKL5 reduced long-term potentiation of the perforant path to the dentate gyrus and augmented feedforward inhibition in this pathway; ex vivo experiments confirmed that excitatory/inhibitory input into the dentate gyrus is skewed toward inhibition. Injecting the GABAergic antagonist gabazine into the dentate improved contextual fear memory in Cdkl5...

Stimulatory coupling of dopamine D1 (D1R) and adenosine A2A receptors (A2AR) to adenylyl cyclase within the striatum is mediated through a specific Gαolfβ2γ7 heterotrimer to ultimately modulate motor behaviors. To dissect the individual roles of the Gαolfβ2γ7 heterotrimer in different populations of medium spiny neurons (MSNs), we produced and characterized conditional mouse models, in which the Gng7 gene was deleted in either the D1R- or A2AR/D2R-expressing MSNs. We show that conditional loss of γ7 disrupts the cell type-specific assembly of the Gαolfβ2γ7 heterotrimer, thereby identifying its circumscribed roles acting downstream of either the D1Rs or A2ARs in coordinating motor behaviors including in vivo responses to psychostimulants. We reveal that Gαolfβ2γ7/cAMP signal in D1R-MSNs does not impact spontaneous and amphetamine-induced locomotor behaviors in male and female mice, while its loss in A2AR/D2R-MSNs results in a hyperlocomotor phenotype and enhanced locomotor response to amphetamine. Additiona...

Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically pre-determined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation, however it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 days after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately-grown and IUGR mouse offspring. We found that IUGR offspring...