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@ARTICLE{Tessitore:285015,
      author       = {Tessitore, Sara and Torazza, Carola and Bonifacino, Tiziana
                      and Bacchetti, Francesca and Roselli, Francesco and Raiteri,
                      Luca and Milanese, Marco and Bonanno, Giambattista},
      title        = {{F}ocus on the excitatory and inhibitory neurotransmission
                      imbalance in amyotrophic lateral sclerosis: a harmful
                      disease player or a potential therapeutic opportunity?},
      journal      = {Neurobiology of disease},
      volume       = {219},
      issn         = {0969-9961},
      address      = {[Amsterdam]},
      publisher    = {Elsevier},
      reportid     = {DZNE-2026-00141},
      pages        = {107272},
      year         = {2026},
      abstract     = {Amyotrophic lateral sclerosis (ALS) is a progressive and
                      fatal neurodegenerative disease affecting both upper and
                      lower motor neurons. Evidence indicates that ALS is a
                      'multifactorial' and 'multicellular' disease; however, the
                      causes of ALS remain elusive, as the mechanisms underlying
                      the disease have not yet been completely clarified. One
                      major proposed mechanism, first described in 1990, is the
                      glutamate excitotoxicity theory. This theory suggests that
                      excessive glutamatergic neurotransmission, combined with
                      impaired glutamate clearance, significantly contributes to
                      motor neuron degeneration. Aberrant glutamate
                      neurotransmission may lead to precocious motor neuron
                      hyperexcitability in the brain cortex and spinal cord, which
                      can be later followed by hypoexcitability phases.
                      Accumulating evidence suggests that impairment in inhibitory
                      neurotransmission is relevant for excitation/inhibition
                      imbalance, leading to excitotoxicity, a critical feature of
                      ALS. Gamma-aminobutyric acid (GABA) and glycine are the
                      primary inhibitory neurotransmitters that modulate neuronal
                      excitability, including that of motor neurons. In ALS,
                      dysfunction of inhibitory processes and loss of cortical and
                      spinal inhibitory interneurons are observed. Renshaw cells,
                      which mediate recurrent inhibition in the spinal cord, seem
                      particularly vulnerable. The interactions among
                      neurotransmitters, including glutamate, GABA, and glycine,
                      play pivotal roles in regulating the excitation/inhibition
                      balance. Auto- or hetero-receptor-mediated interactions are
                      crucial, but auto- or hetero-transporter-mediated
                      neurotransmission control, as well as other molecular
                      mechanisms that regulate neuronal interplay, are also
                      relevant, as they can be altered in pathological conditions
                      such as ALS. To facilitate the search for new effective
                      therapies for ALS, attention toward the impairment of
                      inhibitory neurotransmission is essential to determine the
                      role of excitation/inhibition imbalance on excitotoxicity.
                      Different pharmacological agents are being used to treat
                      other pathologies in which the excitation/inhibition ratio
                      is impaired. Among these, we highlighted the potential of
                      novel glycine and GABA receptor ligands and transporter
                      inhibitors, as stand-alone interventions or in combination
                      with other treatments. The present review aims to elucidate
                      the complex interplay between excitatory and inhibitory
                      neurotransmission in ALS, exploring the potential to target
                      this imbalance for therapeutic purposes.},
      subtyp        = {Review Article},
      keywords     = {Amyotrophic Lateral Sclerosis: physiopathology /
                      Amyotrophic Lateral Sclerosis: metabolism / Amyotrophic
                      Lateral Sclerosis: drug therapy / Humans / Synaptic
                      Transmission: physiology / Animals / Motor Neurons:
                      metabolism / Motor Neurons: physiology / Glutamic Acid:
                      metabolism / Neural Inhibition: physiology / Amyotrophic
                      lateral sclerosis (Other) / Cortex (Other) /
                      Excitation/inhibition balance (Other) / GABA (Other) /
                      Glutamate (Other) / Glycine (Other) / Ion channels (Other) /
                      Receptors (Other) / Spinal cord (Other) / Transporters
                      (Other) / Glutamic Acid (NLM Chemicals)},
      cin          = {AG Roselli},
      ddc          = {570},
      cid          = {I:(DE-2719)1910001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41525888},
      doi          = {10.1016/j.nbd.2026.107272},
      url          = {https://pub.dzne.de/record/285015},
}