Food for thought: linking caloric intake to behavior via sirtuin activity.

Sirtuins are thought to form crucial links between energy levels and cellular metabolism. Libert et al. now provide evidence that SIRT1 activity in the brain modifies mammalian emotional behavior via monoamine signaling and that changes in this pathway might contribute to human affective disorders.

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. Natural manipulation of neurogenesis by aging-to decrease it-and housing in an enriched environment-to increase it-strongly affected the levels of inhibition. We also demonstrated that elevating activity in adult-born GCs in awake behaving animals reduced the overall number of mature GCs activated by exploration. These data suggest that inhibitory modulation of mature GCs may be an important function of adult-born hippocampal neurons. © 2015 Wiley Periodicals, Inc.

Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex.

Individuals with 22q11.2 microdeletions have cognitive and behavioral impairments and the highest known genetic risk for developing schizophrenia. One gene disrupted by the 22q11.2 microdeletion is DGCR8, a component of the "microprocessor" complex that is essential for microRNA production, resulting in abnormal processing of specific brain miRNAs and working memory deficits. Here, we determine the effect of Dgcr8 deficiency on the structure and function of cortical circuits by assessing their laminar organization, as well as the neuronal morphology, and intrinsic and synaptic properties of layer 5 pyramidal neurons in the prefrontal cortex of Dgcr8(+/-) mutant mice. We found that heterozygous Dgcr8 mutant mice have slightly fewer cortical layer 2/4 neurons and that the basal dendrites of layer 5 pyramidal neurons have slightly smaller spines. In addition to the modest structural changes, field potential and whole-cell electrophysiological recordings performed in layer 5 of the prefrontal cortex revealed greater short-term synaptic depression during brief stimulation trains applied at 50 Hz to superficial cortical layers. This finding was accompanied by a decrease in the initial phase of synaptic potentiation. Our results identify altered short-term plasticity as a neural substrate underlying the cognitive dysfunction and the increased risk for schizophrenia associated with the 22q11.2 microdeletions.

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.

Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.

Adult neurogenesis in the mammalian hippocampus: why the dentate gyrus?

In the adult mammalian brain, newly generated neurons are continuously incorporated into two networks: interneurons born in the subventricular zone migrate to the olfactory bulb, whereas the dentate gyrus (DG) of the hippocampus integrates locally born principal neurons. That the rest of the mammalian brain loses significant neurogenic capacity after the perinatal period suggests that unique aspects of the structure and function of DG and olfactory bulb circuits allow them to benefit from the adult generation of neurons. In this review, we consider the distinctive features of the DG that may account for it being able to profit from this singular form of neural plasticity. Approaches to the problem of neurogenesis are grouped as "bottom-up," where the phenotype of adult-born granule cells is contrasted to that of mature developmentally born granule cells, and "top-down," where the impact of altering the amount of neurogenesis on behavior is examined. We end by considering the primary implications of these two approaches and future directions.

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. The hippocampus has been implicated in schizophrenia pathogenesis, is reduced in volume in 22q11.2 deletion carriers and displays altered neuronal structure in a mouse model of the mutation (Df(16)A(+/-) mice). Here we investigate hippocampal CA1 physiology, hippocampal-dependent spatial memory and novelty-induced hippocampal activation in Df(16)A(+/-) mice. We found normal spatial reference memory (as assayed by the Morris water maze test) as well as modest but potentially important deficits in physiology. In particular, a reduction in the level of inhibition of CA1 pyramidal neurons was observed, implying a decrease in interneuron activity. Additionally, deficits in LTP were observed using certain induction protocols. Induction of c-Fos expression by exploration of a novel environment suggested a relative sparing of CA1 and dentate gyrus function but showed a robust decrease in the number of activated CA3 pyramidal neurons in Df(16)A(+/-) mice. Overall, experiments performed in this 22q11.2 deletion model demonstrated deficits of various degrees across different regions of the hippocampus, which together may contribute to the increased risk of developing schizophrenia.

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 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.

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. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene.

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. We also show that both rapidly and slowly adapting currents inactivate as a function of membrane stretch. However, the rapidly adapting current inactivation time course is mainly dependent on channel opening whilst slowly adapting current kinetics are dependent on membrane stretch. In response to repeated stimulation, slowly adapting currents inactivate less and recover more quickly than rapidly adapting currents. Therefore, vibratory stimuli tend to inactivate rapidly adapting currents whilst static stimuli tend to inactivate slowly adapting currents. Current clamp experiments show that, physiologically, the response of different types of sensory neurons is dictated primarily by the static or dynamic nature of the mechanical stimulus and the interplay between voltage-gated and mechanically gated ion channels expressed in these 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+. The structurally related larger dye FM3-25 inhibited mechanically activated currents to a lesser degree and did not permeate the channels. In vivo, FMI-43 decreases pain sensitivity in the Randall-Selitto test and increases the withdrawal threshold from von Frey hairs, together suggesting that the channels expressed at the cell body in culture mediate mechanosensation in the intact animal. These data give further insight into the mechanosensitive ion channels expressed by somatosensory neurons and suggest FM dyes are an interesting tool for studying them.

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. This chapter describes the properties of mechanosensitive channels present in sensory neurons and the potential molecular candidates that may underlie. Mechanically regulated electrical activity by touch and tissue damaging levels of pressure in sensory neurons seems to involve a variety of direct and indirect mechanisms and ion channels, and the involvement of specialized end organs in mechanotransduction complicates matters even more. Imaging studies are providing useful information about the events in the central nervous system associated with touch pain and allodynia (a pathological state where touch becomes painful this type of activity).

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. When presented with different contexts, mature granule cells underwent robust remapping of their spatial representations, and the few spatially tuned adult-born cells remapped to a similar degree. We next used optogenetic silencing to confirm the direct involvement of abGCs in context encoding and discrimination, consistent with their proposed role in pattern separation. These results provide the first in vivo characterization of abGCs and reveal their participation in the encoding of novel information.

Distinct mechanosensitive properties of capsaicin-sensitive and -insensitive sensory neurons.

Mechanical stimulation of the somata of cultured neonatal rat dorsal root ganglia (DRG) neurons evoked inward cationic currents that displayed distinct properties between different subsets of cells. The presumptive nociceptor population, defined by capsaicin sensitivity, showed higher thresholds for the induction of an inward current and lower peak currents than other mechanosensitive neurons. A subset of capsaicin-sensitive IB4-positive sensory neurons was refractory to mechanical stimulation. All mechanically activated currents were blocked by gadolinium (IC50 approximately 8 microm) and ruthenium red (IC50 approximately 3 microm). Disruption of the actin cytoskeleton by acute application of 10 microm cytochalasin B inhibited currents much more effectively in capsaicin-insensitive (61%) than capsaicin-sensitive neurons (20%). Extracellular calcium also attenuated mechanosensitive currents and to a greater degree in capsaicin-insensitive neurons than capsaicin-sensitive neurons. These data demonstrate that the somata of different types of cultured sensory neurons have distinct mechanosensitive phenotypes that retain properties associated with nerve terminal mechanosensors in vivo.

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. This hypothesis was tested by evaluating the response to the chemoconvulsant kainic acid (KA) in mice with reduced adult neurogenesis, produced either by focal X-irradiation of the DG, or by pharmacogenetic deletion of dividing radial glial precursors. In the first 4 hrs after KA administration, when mice have the most robust seizures, mice with reduced adult neurogenesis had more severe convulsive seizures, exhibited either as a decreased latency to the first convulsive seizure, greater number of convulsive seizures, or longer convulsive seizures. Nonconvulsive seizures did not appear to change or they decreased. Four-21 hrs after KA injection, mice with reduced adult neurogenesis showed more interictal spikes (IIS) and delayed seizures than controls. Effects were greater when the anticonvulsant ethosuximide was injected 30 min prior to KA administration; ethosuximide allows forebrain seizure activity to be more easily examined in mice by suppressing seizures dominated by the brainstem. These data support the hypothesis that reduction of adult-born neurons increases the susceptibility of the brain to effects of KA.

Ion channel activities implicated in pathological pain.

Altered expression of voltage-gated sodium, calcium and potassium channels has been associated with neuropathic pain conditions. In addition, roles for the ligand-gated P2X3 and NMDA receptors, as well as pacemaker HCN channels have also been invoked in the pathogenesis of neuropathic pain. In this chapter, evidence of an important role for post-translational regulation of Nav1.9 in setting pain thresholds is presented. Despite the importance of tactile allodynia and mechanical hyperalgesia in chronic pain, we remain ignorant of the molecular nature of mechanosensors present in sensory neurons. A number of candidate mechanosensor genes, identified because of their structural similarity with mechanosensors in Caenorbabditis elegans and Drosophila melanogaster have been identified. Acid-sensing ion channels (ASICs) are structurally related to putative mechanosensors in C. elegans, whilst transient receptor potential channels (TRPs) have been implicated in mechanosensation in the Drosophila acoustic system. Evidence against a role for ASICs as primary transducers of mechanosensation is provided here, and recent evidence implicating TRP channels is reviewed. Finally, the use of sensory neuron-specific gene deletion approaches to unravel the significance of individual ion channels in the regulation of sensory neuron excitability and the induction of pain will be described.

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. In contrast, elevating the activity of GCs in the ventral DG has no effect on contextual learning but powerfully suppresses innate anxiety. These results suggest that strategies aimed at modulating the excitability of the ventral DG may be beneficial for the treatment of anxiety disorders.

The 22q11.2 microdeletion: fifteen years of insights into the genetic and neural complexity of psychiatric disorders.

Over the last fifteen years it has become established that 22q11.2 deletion syndrome (22q11DS) is a true genetic risk factor for schizophrenia. Carriers of deletions in chromosome 22q11.2 develop schizophrenia at rate of 25-30% and such deletions account for as many as 1-2% of cases of sporadic schizophrenia in the general population. Access to a relatively homogeneous population of individuals that suffer from schizophrenia as the result of a shared etiological factor and the potential to generate etiologically valid mouse models provides an immense opportunity to better understand the pathobiology of this disease. In this review we survey the clinical literature associated with the 22q11.2 microdeletions with a focus on neuroanatomical changes. Then, we highlight results from work modeling this structural mutation in animals. The key biological pathways disrupted by the mutation are discussed and how these changes impact the structure and function of neural circuits is described.