GluA4 Dependent Plasticity Mechanisms Contribute to Developmental Synchronization of the CA3–CA1 Circuitry in the Hippocampus

During the course of development, molecular mechanisms underlying activity-dependent synaptic plasticity change considerably. At immature CA3–CA1 synapses in the hippocampus, PKA-driven synaptic insertion of GluA4 AMPA receptors is the predominant mechanism for synaptic strengthening. However, the physiological significance of the developmentally restricted GluA4-dependent plasticity mechanisms is poorly understood. Here we have used microelectrode array (MEA) recordings in GluA4 deficient slice cultures to study the role of GluA4 in early development of the hippocampal circuit function. We find that during the first week in culture (DIV2–6) when GluA4 expression is restricted to pyramidal neurons, loss of GluA4 has no effect on the overall excitability of the immature network, but significantly impairs synchronization of the CA3 and CA1 neuronal populations. In the absence of GluA4, the temporal correlation of the population spiking activity between CA3–CA1 neurons was significantly lower as compared to wild-types at DIV6. Our data show that synapse-level defects in transmission and plasticity mechanisms are efficiently compensated for to normalize population firing rate at the immature hippocampal network. However, lack of the plasticity mechanisms typical for the immature synapses may perturb functional coupling between neuronal sub-populations, a defect frequently implicated in the context of developmentally originating neuropsychiatric disorders.

     

Chromosome length and perinuclear attachment constrain resolution of DNA intertwines

To allow chromosome segregation, topoisomerase II (topo II) must resolve sister chromatid intertwines (SCI) formed during deoxynucleic acid (DNA) replication. How this process extends to the full genome is not well understood. In budding yeast, the unique structure of the ribosomal DNA (rDNA) array is thought to cause late SCI resolution of this genomic region during anaphase. In this paper, we show that chromosome length, and not the presence of rDNA repeats, is the critical feature determining the time of topo II–dependent segregation. Segregation of chromosomes lacking rDNA also requires the function of topo II in anaphase, and increasing chromosome length aggravates missegregation in topo II mutant cells. Furthermore, anaphase Stu2-dependent microtubule dynamics are critical for separation of long chromosomes. Finally, defects caused by topo II or Stu2 impairment depend on attachment of telomeres to the nuclear envelope. We propose that topological constraints imposed by chromosome length and perinuclear attachment determine the amount of SCI that topo II and dynamic microtubules resolve during anaphase.