The Glutamate-GABA System in Atypical Neurodevelopment
Autism Spectrum Disorder (ASD) is a common neurodevelopmental condition typically diagnosed at 2-4 years of age when deficits in social interaction and communication are noted by carers. Our knowledge of ASD is advancing with greater awareness of the needs of autistic children and adults and a move towards improving services for these patients. The underlying neurobiology of ASD is a unifying aetiological agent, likely altered through both genetic and environmental influences. There is compelling evidence to suggest that abnormalities in Excitatory (E) glutamate and inhibitory (I) Gamma-Aminobutyric Acid (GABA) signalling in the brain may underpin ‘atypical’ development. Therefore I chose to examine relationships within the glutamatergic system in the striatum.
First I looked at metabotropic glutamate receptor 5 (mGluR5) in adults with and without ASD and found higher levels of mGluR5 among autistic participants. This is consistent with other recent studies. Despite the close functional ties between mGluR5 and E/I signalling, no-one had directly examined the relationship between mGluR5 and glutamate or GABA in vivo in the human brain of autistic individuals. I found a strong negative relationship between GABA+ and mGluR5. I then looked at mGluR5 in three animal models associated with ASD to see whether any of these models might explain the greater availability of mGluR5 in autism. CNTNAP2 KO mice had significantly higher mGlu5 receptor binding in the striatum (caudate-putamen) as compared to wild-type (WT) mice. Given that CNTNAP2 is associated with a specific striatal deficit of parvalbumin positive GABA interneurons and ‘autistic’ features, this finding suggests that an increase in mGluR5 in ASD may relate to developmental GABAergic interneuron abnormalities.
Neurodevelopment requires careful coordination of neuronal and glial processes spanning proliferation, differentiation, myelination and pruning. Disruption to this process can result in neurodevelopmental difficulties and disorders such as ASD. Therefore I conducted early life studies examining the relationship between subcortical Glx (Glutamate and Glutamine), N-acetylaspartate (a marker of neuronal health) and myo-Inositol (a marker of glial activity) at three early life time points: in utero, within 4 weeks of birth (neonatal time point) and at 4-6-months of age (‘infant’ time point). I compared these to later neurodevelopmental outcomes finding that higher neonatal NAA concentrations corresponded to better general neurodevelopmental scores and lower ADOS-2 scores. As NAA is a marker of neuronal health this implies that we can mark neuronal health at birth and demonstrate that this correlates with neurodevelopmental outcomes. I then went on to examine these same relationships at the 4-6-month timepoint. Higher levels of myo-Inositol (and therefore greater glial activity) corresponded to poorer general and social developmental outcomes. Higher levels of Glx and therefore excess excitation predicted greater social deficits. This is in keeping with the theory of E/I imbalance.
First SupervisorProf. Grainne McAlonan
Second SupervisorProf. Kieran Murphy
CommentsSubmitted for the Award of Doctor of Medicine to RCSI University of Medicine and Health Sciences, 2022
Published CitationCarey C,. The Glutamate-GABA System in Atypical Neurodevelopment. [MD Thesis] Dublin: RCSI University of Medicine and Health Sciences; 2022
- Doctor of Medicine (MD)
Date of award2022-11-30
- Doctor of Medicine (MD)
- Neurological and Psychiatric Disorders