Caloric restriction augments brain glutamic acid decarboxylase‐65 and ‐67 expression

Abstract

The ketogenic diet is a very low-carbohydrate, high-fat diet used to treat refractory epilepsy. We hypothesized that this diet may act by increasing expression of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid (GABA) synthesis. Thus, we evaluated brain GAD levels in a well-established, seizure-suppressing, rodent model of the ketogenic diet. Because the diet is most effective when administered with a modest ( approximately 10%) calorie restriction, we studied three groups of animals: rats fed ad libitum standard rat chow (Ad lib-Std); calorie-restricted standard chow (CR-Std); and an isocaloric, calorie-restricted ketogenic diet (CR-Ket). We found that GAD67 mRNA was significantly increased in the inferior and superior colliculi and cerebellar cortex in both CR diet groups compared with control (e.g., by 45% in the superior colliculus and by 71% in the cerebellar cortex; P <.001). GAD65 mRNA was selectively increased in the superior colliculus and temporal cortex in both CR-Std and CR-Ket diet groups compared with ad lib controls. The only apparent CR-Ket-specific effect was a 30% increase in GAD67 mRNA in the striatum (P =.03). Enhanced GAD immunoreactivity was detected in parallel with the mRNA changes. These data clearly show that calorie restriction increases brain GAD65 and -67 expression in several brain regions, independent of ketogenic effects. These observations may explain why caloric restriction improves the efficacy of the ketogenic diet in treating epilepsy and suggest that diet modification might be useful in treatment of a number of brain disorders characterized by impaired GAD or GABA activity.

Ketogenic diets, mitochondria, and neurological diseases

“…Another study in rats fed the KD for 3 weeks found increased levels of glutamate and glutamine in the hippocampus, but this was also associated with an overall decrease in the transcripts of genes involved in synaptic transmission ( 48 ). Further, using both mild CR (i.e., 90% of daily energy requirements or 10% CR) and an isocaloric KD, investigators found signifi cant increases in the mRNA expression of both isoforms of GAD (GAD65 and GAD67) in several brain regions and independent of ketogenic effects ( 80 ). Additionally, reduced levels of aspartate were found in a mouse model of ketosis, along with the expected increases in acetyl-CoA, with no change in the levels of GABA and glutamate ( 77 ).…”

The Neuropharmacology of the Ketogenic Diet

“…Cheng et al [35] reported that rats fed a calorie-restricted diet for 7 days show increased expression of various glutamic acid decarboxylase isoforms in selected brain regions, including the superior colliculus and cerebellar cortex. However, the changes in expression were similar whether the animals received an ordinary calorie restricted diet or a high-fat, ketogenic diet, indicating that high fat and ketosis do not have specific effects of glutamic acid decarboxylase expression.…”

How does the ketogenic diet induce anti-seizure effects?

“…Yet another study in rats fed the KD for 3 weeks found increased levels of glutamate and glutamine in the hippocampus, but this was also associated with an overall decrease in the transcripts of genes involved in synaptic transmission [20]. Further, using both mild caloric restriction or CR (i.e., 90% of daily energy requirements or 10% CR) and an isocaloric KD, investigators found significant increases in the mRNA expression of both isoforms of GAD (GAD65 and GAD67) in several brain regions which were independent of ketosis [21]. Additionally, reduced levels of aspartate were found in a mouse model of ketosis, along with the expected increases in acetyl-CoA, with no change in the levels of GABA and glutamate [17].…”