Cortical Consequences of In Vivo Blockade of Monocarboxylate Transport During Brain Development in Mice

Abstract

In addition to glucose, monocarboxylates including lactate represent a major source of energy for the developing brain and appears to be crucial in the pathogenesis and recovery after brain damage. We hypothesized a role of monocarboxylates transport in the energy supply of neurons of the immature cerebral cortex. The effects of the blockade of monocarboxylates transport in vivo on the cortical development was investigated in neonatal mice using alphacyano-4-hydroxycinnamate (CIN) diluted either in DMSO (CD) or in ethanol (CE) administered intraperitoneally over postnatal day (P) P1 to P3. Injection of CIN induced a cytoarchitectonic disorganization in the parietal cortex likely due to a combination of slight disturbance of cortical neuronal migration and an increased neuronal cell death observed in CE (p Ͻ 0.05) but not in CD group. An increased number of activated GFAP-positive astroglia was observed in the neocortex in groups treated with CIN (CD and CE) on P10. These data: 1) Provide first evidence of deleterious effects observed in vivo after blockade of monocarboxylates transport in the developing brain; 2) emphasize the role of lactate during neuronal migration as a major source of energy; and 3) suggest the synergistic effect of ethanolinduced hypoglycemia in cortical brain damage induced by CIN. C erebral activity requires delivery of an adequate amount of energy substrates to neurons. In addition to glucose, the main source of energy for the brain, monocarboxylates including lactate play a significant role as alternative energy suppliers (1). Delivery of energy substrates from the blood to the brain requires specific transporters across the endothelial cells involved in blood-brain barrier and cellular membranes of the neurons and glia (2). Therefore, monocarboxylate transporters (MCTs) were supposed to play a key role in astrocyte/ neuronal shuttle as lactate release by astrocytes is likely to be a major energy substrate coupled with neuronal activity as suggested in adults (3). Moreover, monocarboxylate including lactate play a significant role as alternative energy suppliers in developing brain (4) and under challenged conditions including excitotoxic insult or inadequate glucose supply (5-7).Little is known about the energy trafficking during CNS development (4). We previously emphasized the presence of monocarboxylate transporters (MCTs) in the different cell populations of the developing rat cerebral cortex and in the human visual cortex at midgestation including radial glia, mature astrocytes and ependimocytes (8,9). These studies demonstrate that lactate could be used as energy substrate in perinatal period, but physiologic relevance of its trafficking in developing brain have never been studied in vivo.Alpha-cyano-4-hydroxycinnamate (CIN) is a competitive inhibitor of monocarboxylate transporters which is blood brain barrier permeable and appears to block lactate utilization by cells that import monocarboxylates (10). In vitro, using this transporter blocker, lactate has been reporte...

d-Lactic acid-induced neurotoxicity in a calf model

“…In support of this, the serum-CSF L-lactate difference was slightly greater during DL-LA infusion; this may reflect reduced neuronal removal of astrocyte produced L-lactate (Table 2). Similarly, others have shown that blockade of neuronal monocarboxylate transporters responsible for L-lactate entry results in increased neuronal cell death in the developing brain (1).…”

“…In acute ethanol consumption, neurological depression may be caused by low concentrations of circulating tryptophan (3) or interactions with the GABA A receptor complex and facilitation of GABA action (23,58). However, ethanol also has early effects on energy metabolism (1,33,65), which may be similar to some of the actions of D-lactate.…”

Early undernutrition induces glucagon resistance and insulin hypersensitivity in the liver of suckling rats

“…All of these changes in MCTs of restricted pups, here seen for the first time, suggest possible consequences as alterations in synapses. A question arises as to whether the changes in cortical MCTs may also have an impact on lactate transport, whose blockade has deleterious effects in vivo (1). In this regard, it should be noted that MCT2 has the highest affinity for lactate (42).…”

Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

“…However, several findings suggest that glial cells and neurons do not use glucose as a fuel to the same extent: astrocytes take up glucose that is transported across the BECs and use it for the glycolysis, producing lactate that is released into the ISF and subsequently taken up by surrounding neurons [120]. Also, evidences suggest that neurons during development use lactate as an important source of energy during neuronal migration, since in vivo blockade of lactate transport in the brain over postnatal day 1-3 in mice induced a cytoarchitectonic disorganization in the parietal cortex that was likely due to a disturbance of cortical neuronal migration and an increased neuronal cell death [121]. Lactic acid has a pKa of 3.9, thus it exists almost entirely as the lactate anion at physiological pH.…”