Distinct Contribution of Adult-Born Hippocampal Granule Cells to Context Encoding.

Adult-born granule cells (abGCs) have been implicated in cognition and mood; however, it remains unknown how these cells behave in vivo. Here, we have used two-photon calcium imaging to monitor the activity of young abGCs in awake behaving mice. We find that young adult-born neurons fire at a higher rate in vivo but paradoxically exhibit less spatial tuning than their mature counterparts.

Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons.

Robust incorporation of new principal cells into pre-existing circuitry in the adult mammalian brain is unique to the hippocampal dentate gyrus (DG). We asked if adult-born granule cells (GCs) might act to regulate processing within the DG by modulating the substantially more abundant mature GCs. Optogenetic stimulation of a cohort of young adult-born GCs (0 to 7 weeks post-mitosis) revealed that these cells activate local GABAergic interneurons to evoke strong inhibitory input to mature GCs.

Suppression of adult neurogenesis increases the acute effects of kainic acid.

Adult neurogenesis, the generation of new neurons in the adult brain, occurs in the hippocampal dentate gyrus (DG) and the olfactory bulb (OB) of all mammals, but the functions of these new neurons are not entirely clear. Originally, adult-born neurons were considered to have excitatory effects on the DG network, but recent studies suggest a net inhibitory effect. Therefore, we hypothesized that selective removal of newborn neurons would lead to increased susceptibility to the effects of a convulsant.

Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus.

The dentate gyrus (DG), in addition to its role in learning and memory, is increasingly implicated in the pathophysiology of anxiety disorders. Here, we show that, dependent on their position along the dorsoventral axis of the hippocampus, DG granule cells (GCs) control specific features of anxiety and contextual learning. Using optogenetic techniques to either elevate or decrease GC activity, we demonstrate that GCs in the dorsal DG control exploratory drive and encoding, not retrieval, of contextual fear memories.

Evidence for altered hippocampal function in a mouse model of the human 22q11.2 microdeletion.

22q11.2 chromosomal deletions are recurrent copy number mutations that increase the risk of schizophrenia around thirty-fold. Deletion of the orthologous chromosomal region in mice offers an opportunity to characterize changes to neuronal structure and function that may account for the development of this disease.

Kinetic properties of mechanically activated currents in spinal sensory neurons.

Dorsal root ganglion neurons in vitro express a number of types of mechanically activated currents that are thought to underlie somatic mechanosensory transduction in vivo. We have studied the inactivation properties of these currents to assess how they might influence the electrophysiological responses of dorsal root ganglion (DRG) neurons to mechanical stimulation. We show that the speed of ramp-like mechanical stimulation determines the dynamics of mechanically activated current responses and hence the type of DRG neuron most likely to be activated.

Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion.

Individuals with 22q11.2 microdeletions have cognitive deficits and a high risk of developing schizophrenia. Here we provide evidence that primary hippocampal neurons from a mouse model of 22q11.

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice.

The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.

A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition.

DISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired Disc1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity.

High-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain.

Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC(50) 1 microM) sustained mechanically activated currents in a subset of sensory neurons.

FM1-43 is a permeant blocker of mechanosensitive ion channels in sensory neurons and inhibits behavioural responses to mechanical stimuli.

The molecular identity and pharmacological properties of mechanically gated ion channels in sensory neurons are poorly understood. We show that FM1-43, a styryl dye used to fluorescently label cell membranes, permeates mechanosensitive ion channels in cultured dorsal root ganglion neurons, resulting in blockade of three previously defined subtypes of mechanically activated currents. Blockade and dye uptake is voltage dependent and regulated by external Ca2+.

Touch.

Light touch, a sense of muscle position, and the responses to tissue-damaging levels of pressure all involve mechanosensitive sensory neurons that originate in the dorsal root or trigeminal ganglia. A variety of mechanisms of mechanotransduction are proposed. These ranges from direct activation of mechanically activated channels at the tips of sensory neurons to indirect effects of intracellular mediators, or chemical signals released from distended tissues, or specialized mechanosensory end organs.

Modulation of sensory neuron mechanotransduction by PKC- and nerve growth factor-dependent pathways.

Many sensations of pain are evoked by mechanical stimuli, and in inflammatory conditions, sensitivity to such stimuli is commonly increased. Here we used cultured sensory neurons as a model of the peripheral terminal to investigate the effects of inflammatory signaling pathways on mechanosensitive ion channels. Activation of two of these pathways enhanced transduction in a major population of nociceptors.