Reversal of electrophysiological and behavioral deficits mediated by 5-HT7 receptor upregulation following LP-211 treatment in an autistic-like rat model induced by prenatal valproic acid exposure

Article

Author: Javan, Mohammad ; Janahmadi, Mahyar ; Davoudi, Shima ; Hosseinmardi, Narges ; Behzadi, Gila ; Dehghan, Samaneh ; Rahdar, Mona

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by alterations and imbalances in multiple brain neurochemical systems, particularly the serotonergic neurotransmission. This includes changes in serotonin (5-HT) levels, aberrations in 5-HT transporter activity, and decreased synthesis and expression of 5-HT receptors (5-HT7Rs). The exact role of the brain 5-HT system in the development of ASD remains unclear, with conflicting evidence on its involvement. Recently, we have reported research has shown a significant decrease in serotonergic neurons originating from the raphe nuclei and projecting to the CA1 region of the dorsal hippocampus in autistic-like rats. Additionally, we have shown that chronic activation of 5-HT7Rs reverses the effects of autism induction on synaptic plasticity. However, the functional significance of 5-HT7Rs at the cellular level is still not fully understood. This study presents new evidence indicating an upregulation of 5-HT7R in the CA1 subregion of the hippocampus following the induction of autism. The present account also demonstrates that activation of 5-HT7R with its agonist LP-211 can reverse electrophysiological abnormalities in hippocampal pyramidal neurons in a rat model of autism induced by prenatal exposure to VPA. Additionally, in vivo administration of LP-211 resulted in improvements in motor coordination, novel object recognition, and a reduction in stereotypic behaviors in autistic-like offspring. The findings suggest that dysregulated expression of 5-HT7Rs may play a role in the pathophysiology of ASD, and that agonists like LP-211 could potentially be explored as a pharmacological treatment for autism spectrum disorder.

01 Mar 2023·Journal of Neural Transmission

Targeting the brain 5-HT7 receptor to prevent hypomyelination in a rodent model of perinatal white matter injuries

Article

Author: Degos, Vincent ; Jacquens, Alice ; Faivre, Valérie ; Young-Ten, Pierrette ; Zinni, Manuela ; Schwendimann, Leslie ; Galland, Anne ; Le Charpentier, Tifenn ; Csaba, Zsolt ; Van Steenwinckel, Juliette ; Dournaud, Pascal ; Pispisa, Maxime ; Vitalis, Tania ; Bokobza, Cindy ; Gressens, Pierre ; Guenoun, David ; Lebon, Sophie ; Roumier, Anne ; Cruz, Alexandra ; Bianco, Blandine ; Monteiro, Patricia

AbstractApproximately 15 million babies are born prematurely every year and many will face lifetime motor and/or cognitive deficits. Children born prematurely are at higher risk of developing perinatal brain lesions, especially white matter injuries (WMI). Evidence in humans and rodents demonstrates that systemic inflammation-induced neuroinflammation, including microglial and astrocyte reactivity, is the prominent processes of WMI associated with preterm birth. Thus, a new challenge in the field of perinatal brain injuries is to develop new neuroprotective strategies to target neuroinflammation to prevent WMI. Serotonin (5-HT) and its receptors play an important role in inflammation, and emerging evidence indicates that 5-HT may regulate brain inflammation by the modulation of microglial reactivity and astrocyte functions. The present study is based on a mouse model of WMI induced by intraperitoneal (i.p.) injections of IL-1β during the first 5 days of life. In this model, certain key lesions of preterm brain injuries can be summarized by (i) systemic inflammation, (ii) pro-inflammatory microglial and astrocyte activation, and (iii) inhibition of oligodendrocyte maturation, leading to hypomyelination. We demonstrate that Htr7 mRNA (coding for the HTR7/5-HT7 receptor) is significantly overexpressed in the anterior cortex of IL-1β-exposed animals, suggesting it as a potential therapeutic target. LP-211 is a specific high-affinity HTR7 agonist that crosses the blood–brain barrier (BBB). When co-injected with IL-1β, LP-211 treatment prevented glial reactivity, the down-regulation of myelin-associated proteins, and the apparition of anxiety-like phenotypes. Thus, HTR7 may represent an innovative therapeutic target to protect the developing brain from preterm brain injuries.

01 Jan 2023·Frontiers in neuroscience

Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models.

Article

Author: Prokesch, Manuela ; Sharghi, Shirin ; Chagnaud, Boris Philippe ; Lacivita, Enza ; Daurer, Magdalena ; Flunkert, Stefanie ; Hutter-Paier, Birgit ; Leopoldo, Marcello ; Rabl, Roland

IntroductionAutism spectrum disorder (ASD) is a persistent neurodevelopmental condition characterized by two core behavioral symptoms: impaired social communication and interaction, as well as stereotypic, repetitive behavior. No distinct cause of ASD is known so far; however, excitatory/inhibitory imbalance and a disturbed serotoninergic transmission have been identified as prominent candidates responsible for ASD etiology.MethodsThe GABA _B receptor agonist R-Baclofen and the selective agonist for the 5HT₇ serotonin receptor LP-211 have been reported to correct social deficits and repetitive behaviors in mouse models of ASD. To evaluate the efficacy of these compounds in more details, we treated BTBR T⁺ Itpr3 ^tf /J and B6.129P2-Fmr1 ^tm1Cgr /J mice acutely with R-Baclofen or LP-211 and evaluated the behavior of animals in a series of tests.ResultsBTBR mice showed motor deficits, elevated anxiety, and highly repetitive behavior of self-grooming. Fmr1-KO mice exhibited decreased anxiety and hyperactivity. Additionally, Fmr1-KO mice's ultrasonic vocalizations were impaired suggesting a reduced social interest and communication of this strain. Acute LP-211 administration did not affect the behavioral abnormalities observed in BTBR mice but improved repetitive behavior in Fmr1-KO mice and showed a trend to change anxiety of this strain. Acute R-Baclofen treatment improved repetitive behavior only in Fmr1-KO mice.ConclusionOur results add value to the current available data on these mouse models and the respective compounds. Yet, additional studies are needed to further test R-Baclofen and LP-211 as potential treatments for ASD therapy.

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