Metabolic demands, sensory deficits: Tradeoffs in times of scarcity.

The brain requires a lot of energy to carry out its functions at peak performance. In times of energy deficit, something has to give. In this issue of Neuron, Padamsey et al. (2021) explore how metabolic demands impact cortical coding by demonstrating the effects of food restriction on visual processing.

Prominent role of forebrain excitatory neurons in SCN8A encephalopathy.

De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities. The major biophysical effect of the mutation was previously shown to be impaired channel inactivation accompanied by increased current density. We have generated a conditional mouse mutation in which expression of this severe gain-of-function mutation is dependent upon Cre recombinase. Global activation of p.Arg1872Trp by EIIa-Cre resulted in convulsive seizures and lethality at 2 weeks of age. Neural activation of the p.Arg1872Trp mutation by Nestin-Cre also resulted in early onset seizures and death. Restriction of p.Arg1872Trp expression to excitatory neurons using Emx1-Cre recapitulated seizures and juvenile lethality between 1 and 2 months of age. In contrast, activation of p.Arg1872Trp in inhibitory neurons by Gad2-Cre or Dlx5/6-Cre did not induce seizures or overt neurological dysfunction. The sodium channel modulator GS967/Prax330 prolonged survival of mice with global expression of R1872W and also modulated the activity of the mutant channel in transfected cells. Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment. These findings provide insight into the pathogenic mechanism of this gain-of-function mutation of SCN8A and identify excitatory neurons as critical targets for therapeutic intervention.

Sucrose ingestion induces glutamate AMPA receptor phosphorylation in dorsal hippocampal neurons: Increased sucrose experience prevents this effect.

Evidence suggests that meal-related memory influences later eating behavior. Memory can serve as a powerful mechanism for controlling eating behavior because it provides a record of recent intake that likely outlasts most physiological signals generated by ingestion. Dorsal (dHC) and ventral hippocampal (vHC) neurons are critical for memory, and we demonstrated previously that they limit energy intake during the postprandial period. If dHC or vHC neurons control intake through a process that requires memory, then ingestion should increase events necessary for synaptic plasticity in dHC and vHC during the postprandial period. To test this, we determined whether ingesting a sucrose solution induced posttranslational events critical for hippocampal synaptic plasticity: phosphorylation of AMPAR GluA1 subunits at 1) serine 831 (pSer831) and 2) serine 845 (pSer845). We also examined whether increasing the amount of previous experience with the sucrose solution, which would be expected to decrease the mnemonic demand involved in an ingestion bout, would also attenuate sucrose-induced phosphorylation. Quantitative immunoblotting of dHC and vHC membrane fractions demonstrated that sucrose ingestion increased postprandial pSer831 in dHC but not vHC. Increased previous sucrose experience prevented sucrose-induced dHC pSer831. Sucrose ingestion did not affect pSer845 in either dHC or vHC. Thus, the present findings show that ingestion activates a postranslational event necessary for synaptic plasticity in an experience-dependent manner, which is consistent with the hypothesis that dHC neurons form a memory of a meal during the postprandial period.