Subcortical Glutamate Mediates the Reduction of Short-Range Functional Connectivity with Age in a Developmental Cohort

Abstract

Marked changes in brain physiology and structure take place between childhood and adulthood, including changes in functional connectivity and changes in the balance between main excitatory and inhibitory neurotransmitters glutamate (Glu) and GABA. The balance of these neurotransmitters is thought to underlie neural activity in general and functional connectivity networks in particular, but so far no studies have investigated the relationship between human development related differences in these neurotransmitters and concomitant changes in functional connectivity. GABAϩ/H 2 O and Glu/H 2 O levels were acquired in a group of healthy children, adolescents, and adults in a subcortical (basal ganglia) region, as well as in a frontal region in adolescents and adults. Our results showed higher GABAϩ/ Glu with age in both the subcortical and the frontal voxel, which were differentially associated with significantly lower Glu/H 2 O with age in the subcortical voxel and by significantly higher GABAϩ/H 2 O with age in the frontal voxel. Using a seed-to-voxel analysis, we were further able to show that functional connectivity between the putamen (seed) and other subcortical structures was lower with age. Lower subcortical Glu/H 2 O with age mediated the lower connectivity in the dorsal putamen. Based on these results, and the potential role of Glu in synaptic pruning, we suggest that lower Glu mediates a reduction of local connectivity during human development.

Dynamic changes of functional segregation and integration in vulnerability and resilience to schizophrenia

“…Dynamic changes of network characteristics (Barthélemy, 2011;Ghisleni et al, 2015) appeared to be dependent on neurotransmitter milieu. It has been shown that Glu mediates the reduction of short-range connections within subcortical regions including the thalamus, whereas GABA or GABA-dopamine interaction may shape longrange connections in the frontal lobe (Ghisleni et al, 2015). It has been shown that Glu mediates the reduction of short-range connections within subcortical regions including the thalamus, whereas GABA or GABA-dopamine interaction may shape longrange connections in the frontal lobe (Ghisleni et al, 2015).…”

“…While not specifically examined in this study, the present results may be causally linked to the reduction of glutamatergic neurotransmission (Goff & Coyle, 2001) and reduced GABA in the PFC (Gonzalez-Burgos & Lewis, 2008;Lewis, Hashimoto, & Volk, 2005) reported in SZ. Dynamic changes of network characteristics (Barthélemy, 2011;Ghisleni et al, 2015) appeared to be dependent on neurotransmitter milieu. Neurotransmitters, which include inhibitory and excitatory ones, are mainly GABA or glutamate (Glu)-ergic, respectively.…”

“…Neurotransmitters, which include inhibitory and excitatory ones, are mainly GABA or glutamate (Glu)-ergic, respectively. It has been shown that Glu mediates the reduction of short-range connections within subcortical regions including the thalamus, whereas GABA or GABA-dopamine interaction may shape longrange connections in the frontal lobe (Ghisleni et al, 2015). The resultant normative brain architecture is a balance between short-and long-range connections, with predominant short-range connections within the primary sensory and motor cortical areas, and subcortical regions such as thalamus, and predominant long-range connections in heteromodal cortices, consistent with our findings (Sepulcre et al, 2010).…”

“…Study of SZ and HR could identify dynamic changes in functional segregation and integration related to disease vulnerability and resilience in SZ. Brain network function is heavily influenced by neurodevelopment processes (Barthélemy, 2011;Ghisleni et al, 2015). These processes appeared to be dependent on the distance range of neural connections.…”

A novel ecological account of prefrontal cortex functional development.

“…Short term fluctuations in function could arise from changes in allostatic load that occur in response to mismatches between the current input to the PFC and the input that the PFC was previously specialized to process at an earlier state. We suggest that this may activate physiological adaptations to increase processing efficiency, such as by promoting experience-dependent myelination in PFC’s connections with other neural regions (e.g., Markham & Greenough, 2004), by promoting accelerated development of functional connectivity through mediators such as cortisol (e.g., Callaghan & Richardson, 2012, 2014) or excitatory and inhibitory neurotransmitters such as glutamate and GABA (e.g., Ghisleni et al, 2015; Hensch et al, 1998), or by promoting synaptic pruning within PFC (e.g., Selemon, 2013). These physiological responses may help PFC adapt to process increased or more complex input, helping restore allostasis or a net positive energy balance with time.…”