Dynamin 1 isoform roles in a mouse model of severe childhood epileptic encephalopathy.

Dynamin 1 is a large neuron-specific GTPase involved in the endocytosis and recycling of pre-synaptic membranes and synaptic vesicles. Mutations in the gene encoding dynamin 1 (DNM1) underlie two epileptic encephalopathy syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Mice homozygous for the Dnm1 fitful mutation, a non-synonymous coding variant in an alternatively spliced exon of Dnm1 (exon 10a; isoform designation: Dnm1a(Ftfl)) have an epileptic encephalopathy-like disorder including lethal early onset seizures, locomotor and neurosensory deficits. Although fitful heterozygotes have milder recurrent seizures later in life, suggesting an additive or semi-dominant mechanism, the molecular etiology must also consider the fact that Dnm1a(Ftfl) exerts a dominant negative effect on endocytosis in vitro. Another complication is that the fitful mutation induces alterations in the relative abundance of Dnm1 splice variants; mutants have a downregulation of Dnm1a and an upregulation of Dnm1b, changes which may contribute to the epileptic pathology. To examine whether Dnm1a loss of function, Dnm1a(Ftfl) dominance or compensation by Dnm1b is the most critical for severe seizures, we studied alternate isoform-specific mutant mice. Mice lacking Dnm1 exon 10a or Dnm1 exon 10b have neither spontaneous seizures nor other overt abnormalities, suggesting that in normal conditions the major role of each isoform is redundant. However, in the presence of Dnm1a(Ftfl) only exon 10a deleted mice experience severe seizures. These results reveal functional differences between Dnm1a and Dnm1b isoforms in the presence of a challenge, i.e. toxic Dnm1(Ftfl), while reinforcing its effect explicitly in this model of severe pediatric epilepsy. Neurobiol Dis 2016; 95:1-11

Effects of disrupting medial prefrontal cortex GABA transmission on decision-making in a rodent gambling task

Decision-making is a complex cognitive process that is mediated, in part, by subregions of the medial prefrontal cortex (PFC). Decision-making is impaired in a number of psychiatric conditions including schizophrenia. Notably, people with schizophrenia exhibit reductions in GABA function in the same PFC areas that are implicated in decision-making. For example, expression of the GABA-synthesizing enzyme GAD67 is reduced in the dorsolateral PFC of people with schizophrenia. The goal of this experiment was to determine whether disrupting cortical GABA transmission impairs decision-making using a rodent gambling task (rGT). Rats were trained on the rGT until they reached stable performance and then were implanted with guide cannulae aimed at the medial PFC. Following recovery, the effects of intra-PFC infusions of the GABA(A) receptor antagonist bicuculline methiodide (BMI) or the GABA synthesis inhibitor l-allylglycine (LAG) on performance on the rGT were assessed. Intracortical infusions of BMI (25 ng/mu l/side), but not LAG (10 mu g/mu l/side), altered decision-making. Following BMI infusions, rats made fewer advantageous choices. Follow-up experiments suggested that the change in decision-making was due to a change in the sensitivity to the punishments, rather than a change in the sensitivity to reward magnitudes, associated with each outcome. LAG infusions increased premature responding, a measure of response inhibition, but did not affect decision-making. Blocking GABA(A) receptors, but not inhibiting cortical GABA synthesis, within the medial PFC affects decision-making in the rGT. These data provide proof-of-concept evidence that disruptions in GABA transmission can contribute to the decision-making deficits in schizophrenia