Neuroscience
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Progressive myoclonic epilepsies (PMEs) comprise a group of rare disorders of different genetic aetiologies, leading to childhood-onset myoclonus, myoclonic seizures and subsequent neurological decline. One of the genetic causes for PME, a mutation in the gene coding for Golgi SNAP receptor 2 (GOSR2), gives rise to a PME-subtype prevalent in Northern Europe and hence referred to as North Sea Progressive Myoclonic Epilepsy (NS-PME). Treatment for NS-PME, as for all PME subtypes, is symptomatic; the pathophysiology of NS-PME is currently unknown, precluding targeted therapy. ⋯ Downregulation of the Drosophila GOSR2-orthologue Membrin leads to heat-induced seizure-like behaviour. Specific downregulation of GOSR2/Membrin in glia but not in neuronal cells resulted in a similar phenotype, which was progressive as the flies aged and was partially responsive to treatment with sodium barbital. Our data suggest a role for GOSR2 in glia in the pathophysiology of NS-PME.
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Given the fact that both melatonin and nicotinamide mononucleotide (NMN) act as pleiotropic agents in various age-related cognitive disorders, we aimed to investigate the effect of these compounds separately and together on the cognitive outcomes, mitochondrial function, and apoptosis in aged rats. Forty old and ten young (24 and 3 months old, respectively) male Wistar rats were randomly allocated into five groups: Young+Normal saline (NS), Aged+NS, Aged+Melatonin, Aged+NMN, and Aged+melatonin+NMN. Melatonin (10 mg/kg) and NMN (100 mg/kg) were administered, separately or in combination for 28 every other day in aged animals. ⋯ Behavioral results revealed that NMN and melatonin separately or in combination, alleviate aging-induced memory impairment. Moreover, agents' co-administration declined mitochondrial dysfunction and apoptotic cell count both in PFC and HIP regions. The agents separately or in combination (more potent) could induce neuroprotective effect and improve learning and memory in aged animals.
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Sex and ovarian function contribute to hypertension susceptibility, however, the mechanisms are not well understood. Prior studies show that estrogens and neurogenic factors, including hypothalamic glutamatergic NMDA receptor plasticity, play significant roles in rodent hypertension. Here, we investigated the role of sex and ovarian failure on AMPA receptor plasticity in estrogen-sensitive paraventricular nucleus (PVN) neurons in naïve and angiotensin II (AngII) infused male and female mice and female mice at early and late stages of accelerated ovarian failure (AOF). ⋯ Significantly, only late stage-AOF female mice infused with AngII had an increase in GluA1 near the plasma membrane in dendrites of ERβ-expressing PVN neurons. In contrast, prior studies reported that plasmalemmal NMDA GluN1 increased in ERβ-expressing PVN dendrites in males and early, but not late stage AOF females. Together, these findings reveal that early and late stage AOF female mice display unique molecular signatures of long-lasting synaptic strength prior to, and following hypertension.
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Several reports of augmented hyperpolarisation-activated cyclic nucleotide-gated (HCN) currents in seizures have suggested a pro-convulsive identity for HCN channels. The mutations identified in one or more of the four HCN channel subunits are found to be contributing to different epileptic phenotypes. S126L, S632W, V246M and E515K are four different mutations affecting the HCN2 subunit and have been reported in febrile seizures and partial/generalised idiopathic epilepsies. ⋯ Their effects on excitability were studied by observing resting membrane potentials, input resistances and plasticity profiles for measuring the sliding modification threshold (SMT) of Bienenstock-Cooper-Munro (BCM) theory. Virtual knockouts of ion channels other than HCN were also performed to assess their role in altering excitability when they act alongside HCN2 mutations. Our results show that HCN2 mutations can potentially be a primary causative factor for excessive action potential firing through their effect on resting membrane potentials and input resistance.
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Two issues were examined regarding the trigeminal system in larval lampreys: (1) for normal animals, double labeling was used to confirm that the trigeminal system has a topological organization; (2) following trigeminal nerve root transections, double labeling was used to test whether the topological organization of the trigeminal system is restored. First, for normal animals, Alexa 488 dextran amine applied to the medial oral hood (anterior head) labeled trigeminal motoneurons (MNs) in the ventromedial part of the trigeminal motor nuclei (nVm) and axons of trigeminal sensory neurons (SNs) in the ventromedial part of the trigeminal descending tracts (dV). Also, Texas red dextran amine (TRDA) applied to the lateral oral hood labeled trigeminal MNs in the dorsolateral nVm and sensory axons in the dorsolateral dV. ⋯ In addition, double labeling indicated a restoration and refinement of the topological organization of the trigeminal system with increasing recovery times, but mainly for nVm. Despite the paucity of growth of trigeminal sensory axons in dV even at long recovery times (12-16 wks), a substantial percentage of experimental animals recovered trigeminal-evoked swimming responses and trigeminal-evoked synaptic responses in reticulospinal (RS) neurons. Following trigeminal nerve root injury, several mechanisms, including axonal guidance cues, probably contribute to the substantial restoration of the topological organization of the lamprey trigeminal system.