Alterations in Hippocampal Inhibitory Synaptic Transmission in the R6/2 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a genetic neurodegenerative disorder of the central nervous system characterized by choreatic movements, behavioral and psychiatric disturbances and cognitive impairments. Deficits in learning and memory are often the first signs of disease onset in both HD patients and mouse models of HD and are in part regulated by the hippocampus. In the R6/2 mouse model of HD, GABAergic transmission can be excitatory in the hippocampus and restoring inhibition can rescue the associated memory deficits.

Restoring GABAergic inhibition rescues memory deficits in a Huntington's disease mouse model.

Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice.

Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition.

KCC2 is a neuron-specific K-Cl cotransporter essential for establishing the Cl gradient required for hyperpolarizing inhibition in the central nervous system (CNS). KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to human neurological disorders including epilepsy and neuropathic pain.

A kainate receptor subunit promotes the recycling of the neuron-specific K-Cl co-transporter KCC2 in hippocampal neurons.

Synaptic inhibition depends on a transmembrane gradient of chloride, which is set by the neuron-specific K-Cl co-transporter KCC2. Reduced KCC2 levels in the neuronal membrane contribute to the generation of epilepsy, neuropathic pain, and autism spectrum disorders; thus, it is important to characterize the mechanisms regulating KCC2 expression. In the present study, we determined the role of KCC2-protein interactions in regulating total and surface membrane KCC2 expression.

Top-down modulation of olfactory-guided behaviours by the anterior olfactory nucleus pars medialis and ventral hippocampus.

Olfactory processing is thought to be actively modulated by the top-down input from cortical regions, but the behavioural function of these signals remains unclear. Here we find that cortical feedback from the anterior olfactory nucleus pars medialis (mAON) bidirectionally modulates olfactory sensitivity and olfaction-dependent behaviours. To identify a limbic input that tunes this mAON switch, we further demonstrate that optogenetic stimulation of ventral hippocampal inputs to the mAON is sufficient to alter olfaction-dependent behaviours.

Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders.

A key challenge in understanding and ultimately treating autism is to identify common molecular mechanisms underlying this genetically heterogeneous disorder. Transcriptomic profiling of autistic brains has revealed correlated misregulation of the neuronal splicing regulator nSR100/SRRM4 and its target microexon splicing program in more than one-third of analyzed individuals. To investigate whether nSR100 misregulation is causally linked to autism, we generated mutant mice with reduced levels of this protein and its target splicing program.

Neto2-null mice have impaired GABAergic inhibition and are susceptible to seizures.

Neto2 is a transmembrane protein that interacts with the neuron-specific K(+)-Cl(-) cotransporter (KCC2) in the central nervous system (CNS). Efficient KCC2 transport is essential for setting the neuronal Cl(-) gradient, which is required for fast GABAergic inhibition. Neto2 is required to maintain the normal abundance of KCC2 in neurons, and increases KCC2 function by binding to the active oligomeric form of this cotransporter.

Ca2+-induced uncoupling of Aplysia bag cell neurons.

Electrical transmission is a dynamically regulated form of communication and key to synchronizing neuronal activity. The bag cell neurons of Aplysia are a group of electrically coupled neuroendocrine cells that initiate ovulation by secreting egg-laying hormone during a prolonged period of synchronous firing called the afterdischarge. Accompanying the afterdischarge is an increase in intracellular Ca2+ and the activation of protein kinase C (PKC).

Electrical coupling between Aplysia bag cell neurons: characterization and role in synchronous firing.

In neuroendocrine cells, hormone release often requires a collective burst of action potentials synchronized by gap junctions. This is the case for the electrically coupled bag cell neurons in the reproductive system of the marine snail, Aplysia californica. These neuroendocrine cells are found in two clusters, and fire a synchronous burst, called the afterdischarge, resulting in neuropeptide secretion and the triggering of ovulation.

Retinal region of polarization sensitivity switches during ontogeny of rainbow trout.

Polarization sensitivity (PS) in vertebrate vision is controversial, perhaps because its underlying mechanism has remained obscure. An issue that might have added to the controversy is that rainbow trout (Oncorhynchus mykiss), which have served as the primary model system for polarization-based orientation, lose their ability to orient relative to celestial polarized-light patterns when parr (fry) transform into migratory smolts (juveniles), which would benefit most from polarization-based orientation. Here we addressed two key questions: (1) what is the mechanism underling PS?, and (2) how can the paradoxical loss of PS in trout smolts be reconciled? We assessed PS from optic nerve recordings in parr and smolts and found that the retinal region with enhanced PS shifted from the ventral retina in parr to the dorsal retina in smolts.