Network dysfunction precedes neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.

Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence indicates that TDP-43 pathology induces neuronal hyperexcitability, which may contribute to excitotoxic neuronal death. To characterize TDP-43 mediated network excitability changes in a disease-relevant model, we performed in vivo continuous electroencephalography monitoring and ex vivo acute hippocampal slice electrophysiology in rNLS8 mice (males and females), which express human TDP-43 with a defective nuclear localization signal (hTDP-43ΔNLS).

Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.

Unlabelled: Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43ΔNLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration.

Combined RhoA morpholino and ChABC treatment protects identified lamprey neurons from retrograde apoptosis after spinal cord injury.

Previously, we reported that RhoA knockdown by morpholino antisense oligonucleotides (MOs), and enzymatic digestion of chondroitin sulfate proteoglycans (CSPGs) at the site of injury with chondroitinase ABC (ChABC), each can reduce retrograde neuronal apoptosis after spinal cord transection in the lamprey. To elucidate the mechanisms in neuronal survival and axon regeneration, we have investigated whether these two effects are additive . We used lampreys as a spinal cord injury model.

The Composition and Cellular Sources of CSPGs in the Glial Scar After Spinal Cord Injury in the Lamprey.

Axon regrowth after spinal cord injury (SCI) is inhibited by several types of inhibitory extracellular molecules in the central nervous system (CNS), including chondroitin sulfate proteoglycans (CSPGs), which also are components of perineuronal nets (PNNs). The axons of lampreys regenerate following SCI, even though their spinal cords contain CSPGs, and their neurons are enwrapped by PNNs. Previously, we showed that by 2 weeks after spinal cord transection in the lamprey, expression of CSPGs increased in the lesion site, and thereafter, decreased to pre-injury levels by 10 weeks.

Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey.

Paralysis following spinal cord injury (SCI) is due to failure of axonal regeneration. It is believed that axon growth is inhibited by the presence of several types of inhibitory molecules in central nervous system (CNS), including the chondroitin sulfate proteoglycans (CSPGs). Many studies have shown that digestion of CSPGs with chondroitinase ABC (ChABC) can enhance axon growth and functional recovery after SCI.

Source of Early Regenerating Axons in Lamprey Spinal Cord Revealed by Wholemount Optical Clearing with BABB.

Many studies of axon regeneration in the lamprey focus on 18 pairs of large identified reticulospinal (RS) neurons, whose regenerative abilities have been individually quantified. Their axons retract during the first 2 weeks after transection (TX), and many grow back to the site of injury by 4 weeks. However, locomotor movements begin before 4 weeks and the lesion is invaded by axons as early as 2 weeks post-TX.

Mechanisms of Axon Elongation Following CNS Injury: What Is Happening at the Axon Tip?

After an injury to the central nervous system (CNS), functional recovery is limited by the inability of severed axons to regenerate and form functional connections with appropriate target neurons beyond the injury. Despite tremendous advances in our understanding of the mechanisms of axon growth, and of the inhibitory factors in the injured CNS that prevent it, disappointingly little progress has been made in restoring function to human patients with CNS injuries, such as spinal cord injury (SCI), through regenerative therapies. Clearly, the large number of overlapping neuron-intrinsic and -extrinsic growth-inhibitory factors attenuates the benefit of neutralizing any one target.

PTPσ Knockdown in Lampreys Impairs Reticulospinal Axon Regeneration and Neuronal Survival After Spinal Cord Injury.

Traumatic spinal cord injury (SCI) results in persistent functional deficits due to the lack of axon regeneration within the mammalian CNS. After SCI, chondroitin sulfate proteoglycans (CSPGs) inhibit axon regrowth putative interactions with the LAR-family protein tyrosine phosphatases, PTPσ and LAR, localized on the injured axon tips. Unlike mammals, the sea lamprey, , robustly recovers locomotion after complete spinal cord transection (TX).

Heterogeneity in the regenerative abilities of central nervous system axons within species: why do some neurons regenerate better than others?

Some neurons, especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system (CNS) regenerate after axotomy, while most mammalian CNS neurons fail to regenerate. There is an emerging consensus that neurons have different intrinsic regenerative capabilities, which theoretically could be manipulated therapeutically to improve regeneration. Population-based comparisons between "good regenerating" and "bad regenerating" neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret.

Role of axon resealing in retrograde neuronal death and regeneration after spinal cord injury.

Spinal cord injury leads to persistent behavioral deficits because mammalian central nervous system axons fail to regenerate. A neuron's response to axon injury results from a complex interplay of neuron-intrinsic and environmental factors. The contribution of axotomy to the death of neurons in spinal cord injury is controversial because very remote axotomy is unlikely to result in neuronal death, whereas death of neurons near an injury may reflect environmental factors such as ischemia and inflammation.

RhoA activation in axotomy-induced neuronal death.

After spinal cord injury (SCI) in mammals, severed axons fail to regenerate, due to both extrinsic inhibitory factors, e.g., the chondroitin sulfate proteoglycans (CSPGs) and myelin-associated growth inhibitors (MAIs), and a developmental loss of intrinsic growth capacity.

The Effect of Axon Resealing on Retrograde Neuronal Death after Spinal Cord Injury in Lamprey.

Failure of axon regeneration in the central nervous system (CNS) of mammals is due to both extrinsic inhibitory factors and to neuron-intrinsic factors. The importance of intrinsic factors is illustrated in the sea lamprey by the 18 pairs of large, individually identified reticulospinal (RS) neurons, whose axons are located in the same spinal cord tracts but vary greatly in their ability to regenerate after spinal cord transection (TX). The neurons that are bad regenerators also undergo very delayed apoptosis, signaled early by activation of caspases.

The role of RhoA in retrograde neuronal death and axon regeneration after spinal cord injury.

Paralysis following spinal cord injury (SCI) is due to interruption of axons and their failure to regenerate. It has been suggested that the small GTPase RhoA may be an intracellular signaling convergence point for several types of growth-inhibiting extracellular molecules. Even if this is true in vitro, it is not clear from studies in mammalian SCI, whether the effects of RhoA manipulations on axon growth in vivo are due to a RhoA-mediated inhibition of true regeneration or only of collateral sprouting from spared axons, since work on SCI generally is performed with partial injury models.

Protein synthetic machinery and mRNA in regenerating tips of spinal cord axons in lamprey.

Polyribosomes, mRNA, and other elements of translational machinery have been reported in peripheral nerves and in elongating injured axons of sensory neurons in vitro, primarily in growth cones. Evidence for involvement of local protein synthesis in regenerating central nervous system (CNS) axons is less extensive. We monitored regeneration of back-labeled lamprey spinal axons after spinal cord transection and detected mRNA in axon tips by in situ hybridization and microaspiration of their axoplasm.

Antisense Morpholino Oligonucleotides Reduce Neurofilament Synthesis and Inhibit Axon Regeneration in Lamprey Reticulospinal Neurons.

The sea lamprey has been used as a model for the study of axonal regeneration after spinal cord injury. Previous studies have suggested that, unlike developing axons in mammal, the tips of regenerating axons in lamprey spinal cord are simple in shape, packed with neurofilaments (NFs), and contain very little F-actin. Thus it has been proposed that regeneration of axons in the central nervous system of mature vertebrates is not based on the canonical actin-dependent pulling mechanism of growth cones, but involves an internal protrusive force, perhaps generated by the transport or assembly of NFs in the distal axon.

Increased mortality persists in an adult drug-resistant epilepsy prevalence cohort.

Objective: To investigate the cumulative probability of death and the standardised mortality ratio (SMR) in an adult drug-resistant epilepsy (DRE) population.

Methods: In two separate centres during 2003-2006, we identified a total of 433 patients with DRE defined as at least one seizure per month and failure of at least two antiepileptic drugs. These patients were subsequently followed for a total follow-up of 6 years.

Remission and relapse in a drug-resistant epilepsy population followed prospectively.

Purpose: We investigated the cumulative probability of seizure remission and relapse in an adult population with drug-resistant epilepsy and frequent seizures. In addition, we determined clinical predictors of remission and relapse in this population.

Methods: IN 2003, we identified 246 patients at a single center with drug-resistant epilepsy defined as at least one seizure per month and failure of at least two antiepileptic drugs.