The sea lamprey GABAB receptor. Changes after spinal cord injury and its role in axonal regeneration

Spinal cord injury (SCI) causes irreversible loss of function. In contrast to mammals, lampreys show an amazing capacity for spontaneous recovery after a complete SCI. They provide an interesting model to understand the molecular processes that lead to spontaneous recovery. In this study, we analysed the changes in the expression of both gabab subunits after a complete SCI. Our results showed that plastic changes in this system probably contribute to the recovery of function after SCI in lampreys. Pharmacological and genetic manipulations revealed that endogenous GABA acting through GABAB receptors promotes axonal regeneration of descending neurons after a complete SCI in lampreys

Editorial: New challenges and future perspectives in neurodegeneration

Over the last decade, there has been growing interest and important developments in neurodegeneration research. These advances have been fostered by improvements in the research techniques that enable us to collect novel data understand the disease process(es) and underlying mechanisms better. In this Research Topic, we encouraged researchers to summarize their state-of-the-art methods, findings, and the main challenges that the field of neurodegeneration is facing..

Cloning of the GABAB Receptor Subunits B1 and B2 and their Expression in the Central Nervous System of the Adult Sea Lamprey

In vertebrates, γ-aminobutyric acid (GABA) is the main inhibitory transmitter in the central nervous system (CNS) acting through ionotropic (GABAA) and metabotropic (GABAB) receptors. The GABAB receptor produces a slow inhibition since it activates second messenger systems through the binding and activation of guanine nucleotide-binding proteins [G-protein-coupled receptors (GPCRs)]. Lampreys are a key reference to understand molecular evolution in vertebrates. The importance of the GABAB receptor for the modulation of the circuits controlling locomotion and other behaviors has been shown in pharmacological/physiological studies in lampreys. However, there is no data about the sequence of the GABAB subunits or their expression in the CNS of lampreys. Our aim was to identify the sea lamprey GABAB1 and GABAB2 transcripts and study their expression in the CNS of adults. We cloned two partial sequences corresponding to the GABAB1 and GABAB2 cDNAs of the sea lamprey as confirmed by sequence analysis and comparison with known GABAB sequences of other vertebrates. In phylogenetic analyses, the sea lamprey GABAB sequences clustered together with GABABs sequences of vertebrates and emerged as an outgroup to all gnathostome sequences. We observed a broad and overlapping expression of both transcripts in the entire CNS. Expression was mainly observed in neuronal somas of the periventricular regions including the identified reticulospinal cells. No expression was observed in identifiable fibers. Comparison of our results with those reported in other vertebrates indicates that a broad and overlapping expression of the GABAB subunits in the CNS is a conserved character shared by agnathans and gnathostomesS

Full Anatomical Recovery of the Dopaminergic System after a Complete Spinal Cord Injury in Lampreys

Following a spinal injury, lampreys at first are paralyzed below the level of transection. However, they recover locomotion after several weeks, and this is accompanied by the regeneration of descending axons from the brain and the production of new neurons in the spinal cord. Here, we aimed to analyse the changes in the dopaminergic system of the sea lamprey after a complete spinal transection by studying the changes in dopaminergic cell numbers and dopaminergic innervation in the spinal cord. Changes in the expression of the D2 receptor were also studied. We report the full anatomical regeneration of the dopaminergic system after an initial decrease in the number of dopaminergic cells and fibres. Numbers of dopaminergic cells were recovered rostrally and caudally to the site of injury. Quantification of dopaminergic profiles revealed the full recovery of the dopaminergic innervation of the spinal cord rostral and caudal to the site of injury. Interestingly, no changes in the expression of the D2 receptor were observed at time points in which a reduced dopaminergic innervation of the spinal cord was observed. Our observations reveal that in lampreys a spinal cord injury is followed by the full anatomical recovery of the dopaminergic system.This work was funded by the Spanish Ministry of Science and Innovation, Grant no. BFU2010–17174, to María Celina Rodicio. Sonia Gómez-Fernández and Antón Barreiro-Iglesias were supported by predoctoral and postdoctoral grants, respectively, from the Xunta de Galicia (Galicia, Spain)S

Inhibition of gamma-secretase promotes axon regeneration after a complete spinal cord injury

In a recent study, we showed that GABA and baclofen (a GABAB receptor agonist) inhibit caspase activation and promote axon regeneration in descending neurons of the sea lamprey brainstem after a complete spinal cord injury (Romaus-Sanjurjo et al., 2018a). Now, we repeated these treatments and performed 2 independent Illumina RNA-Sequencing studies in the brainstems of control and GABA or baclofen treated animals. GABA treated larval sea lampreys with their controls were analyzed 29 days after a complete spinal cord injury and baclofen treated larvae with their controls 9 days after the injury. One of the most significantly downregulated genes after both treatments was a HES gene (HESB). HES proteins are transcription factors that are key mediators of the Notch signaling pathway and gamma-secretase activity is crucial for the activation of this pathway. So, based on the RNA-Seq results we subsequently treated spinal cord injured larval sea lampreys with a novel gamma-secretase inhibitor (PF-3804014). This treatment also reduced the expression of HESB in the brainstem and significantly enhanced the regeneration of individually identifiable descending neurons after a complete spinal cord injury. Our results show that gamma-secretase could be a novel target to promote axon regeneration after nervous system injuriesGrant sponsors: FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación (Grant number: BFU-2017-87079-P) and the Xunta de Galicia (Grant number: ED431C 2018/28). DR was supported by the BBSRC Institute Strategic Programme Grants to the Roslin Institute (BB/P013732/1, BB/P013740/1, and BB/P013759/1)S

Association of periodontitis with cognitive decline and its progression: Contribution of blood‐based biomarkers of Alzheimer's disease to this relationship

Aim To assess whether periodontitis is associated with cognitive decline and its progression as well as with certain blood-based markers of Alzheimer's disease. Materials and Methods Data from a 2-year follow-up prospective cohort study (n = 101) was analysed. Participants with a previous history of hypertension and aged ≥60 years were included in the analysis. All of them received a full-mouth periodontal examination and cognitive function assessments (Addenbrooke's Cognitive Examination (ACE) and Mini-Mental State Examination [MMSE]). Plasma levels of amyloid beta (Aβ)1-40, Aβ1-42, phosphorylated and total Tau (p-Tau and t-Tau) were determined at baseline, 12 and 24 months. Results Periodontitis was associated with poor cognitive performance (MMSE: β = −1.5 [0.6]) and progression of cognitive impairment (hazard ratio [HR] = 1.8; 95% confidence interval: 1.0–3.1). Subjects with periodontitis showed greater baseline levels of p-Tau (1.6 [0.7] vs. 1.2 [0.2] pg/mL, p < .001) and Aβ1-40 (242.1 [77.3] vs. 208.2 [73.8] pg/mL, p = .036) compared with those without periodontitis. Concentrations of the latter protein also increased over time only in the periodontitis group (p = .005). Conclusions Periodontitis is associated with cognitive decline and its progression in elderly patients with a previous history of hypertension. Overexpression of p-Tau and Aβ1-40 may play a role in this associationThis study was partially supported by grants from the Xunta de Galicia (TS & JC: IN607A2018/3, TS: IN607D 2020/09 and IN607A2022/07), Institute of Health Carlos III (TS: PI22/00938 and CB22/05/00067) and Spanish Ministry of Science (TS: RTI2018-102165-B-I00 and RTC2019-007373-1). Furthermore, this study was also supported by grants from the INTERREG Atlantic Area (TS: EAPA_791/2018_NEUROATLANTIC project), INTER-REG V A España Portugal (POCTEP) (TS: 0624_2IQBIONEURO_6_E) and the European Regional Development Fund. Moreover, several members of the research team are supported by the Institute of Health Carlos III: MAN holds an iPFIS contract (IFI18/00008), DR-S and YL are recipients of a Sara Borrell fellowship (CD21/00166 and CD22/00051, respectively) and TS held a Miguel Servet contract (CPII17/00027). Finally, AC is supported by a predoc contract of Xunta de Galicia (IN606A-2021/015). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscriptS

Serotonin inhibits axonal regeneration of identifiable descending neurons after a complete spinal cord injury in lampreys

Classical neurotransmitters are mainly known for their roles as neuromodulators, but they also play important roles in the control of developmental and regenerative processes. Here, we used the lamprey model of spinal cord injury to study the effect of serotonin in axon regeneration at the level of individually identifiable descending neurons. Pharmacological and genetic manipulations after a complete spinal cord injury showed that endogenous serotonin inhibits axonal regeneration in identifiable descending neurons through the activation of serotonin 1A receptors and a subsequent decrease in cyclic adenosine monophosphate (cAMP) levels. RNA sequencing revealed that changes in the expression of genes that control axonal guidance could be a key factor determining the serotonin effects during regeneration. This study provides new targets of interest for research in non-regenerating mammalian models of traumatic central nervous system injuries and extends the known roles of serotonin signalling during neuronal regeneration. This article has an associated First Person interview with the first author of the paper

GABA promotes survival and axonal regeneration in identifiable descending neurons after spinal cord injury in larval lampreys

The poor regenerative capacity of descending neurons is one of the main causes of the lack of recovery after spinal cord injury (SCI). Thus, it is of crucial importance to find ways to promote axonal regeneration. In addition, the prevention of retrograde degeneration leading to the atrophy/death of descending neurons is an obvious prerequisite to activate axonal regeneration. Lampreys show an amazing regenerative capacity after SCI. Recent histological work in lampreys suggested that GABA, which is massively released after a SCI, could promote the survival of descending neurons. Here, we aimed to study if GABA, acting through GABAB receptors, promotes the survival and axonal regeneration of descending neurons of larval sea lampreys after a complete SCI. First, we used in situ hybridization to confirm that identifiable descending neurons of late-stage larvae express the gabab1 subunit of the GABAB receptor. We also observed an acute increase in the expression of this subunit in descending neurons after SCI, which further supported the possible role of GABA and GABAB receptors in promoting the survival and regeneration of these neurons. So, we performed gain and loss of function experiments to confirm this hypothesis. Treatments with GABA and baclofen (GABAB agonist) significantly reduced caspase activation in descending neurons 2 weeks after a complete SCI. Long-term treatments with GABOB (a GABA analogue) and baclofen significantly promoted axonal regeneration of descending neurons after SCI. These data indicate that GABAergic signalling through GABAB receptors promotes the survival and regeneration of descending neurons after SCI. Finally, we used morpholinos against the gabab1 subunit to knockdown the expression of the GABAB receptor in descending neurons. Long-term morpholino treatments caused a significant inhibition of axonal regeneration. This shows that endogenous GABA promotes axonal regeneration after a complete SCI in lampreys by activating GABAB receptorsGrant sponsors: Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund 2007–2013 (Grant number: BFU2014-56300-P) and Xunta de Galicia (Grant number: GPC2014/030). D.R.-S. was supported by a fellowship from EMBO (Ref.: 7010) to carry out a short-term stay at the laboratory of JRM. A.B.-I. was supported by a grant from the Xunta de Galicia (Grant number: 2016-PG008) and a grant from the crowdfunding platform Precipita (FECYT; Spanish Ministry of Economy and Competitiveness; grant number 2017-CP081)S

Alzheimer&rsquo;s Disease Seen through the Eye: Ocular Alterations and Neurodegeneration

Alzheimer&rsquo;s Disease (AD) is one of the main neurodegenerative diseases worldwide. Unfortunately, AD shares many similarities with other dementias at early stages, which impedes an accurate premortem diagnosis. Therefore, it is urgent to find biomarkers to allow for early diagnosis of the disease. There is increasing scientific evidence highlighting the similarities between the eye and other structures of the CNS, suggesting that knowledge acquired in eye research could be useful for research and diagnosis of AD. For example, the retina and optic nerve are considered part of the central nervous system, and their damage can result in retrograde and anterograde axon degeneration, as well as abnormal protein aggregation. In the anterior eye segment, the aqueous humor and tear film may be comparable to the cerebrospinal fluid. Both fluids are enriched with molecules that can be potential neurodegenerative biomarkers. Indeed, the pathophysiology of AD, characterized by cerebral deposits of amyloid-beta (A&beta;) and tau protein, is also present in the eyes of AD patients, besides numerous structural and functional changes observed in the structure of the eyes. Therefore, all this evidence suggests that ocular changes have the potential to be used as either predictive values for AD assessment or as diagnostic tools