Using a genetic mouse model that faithfully recapitulates a
genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within ...the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltage-dependent potassium channel subunit K
1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of K
1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to K
1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.
Schizophrenia is a profoundly disabling psychiatric illness with a devastating impact not only upon the afflicted but also upon their families and the broader society. Although the underlying causes of schizophrenia remain poorly understood, a growing body of studies has identified and strongly implicated various specific risk genes in schizophrenia pathogenesis. Here, using a genetic mouse model, we explored the impact of one of the most highly penetrant schizophrenia risk genes,
, upon the medial prefrontal cortex, the region believed to be most prominently dysfunctional in schizophrenia. We found substantial derangements in both neuronal excitability and short-term synaptic plasticity-parameters that critically govern neural circuit information processing-suggesting that similar changes may critically, and more broadly, underlie the neural computational dysfunction prototypical of schizophrenia.
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.
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.
The phospholipase protein superfamily plays an important role in hormonal signalling and cellular responses to environmental stimuli. There is also growing evidence for interactions between ...phospholipases and the cytoskeleton. In this report we used a pharmacological approach to investigate whether inhibiting a member of the phospholipase superfamily, phospholipase C (PLC), affects microtubules and actin microfilaments as well as root growth and morphology of Arabidopsis thaliana seedlings. Inhibiting PLC activity using the aminosteroid U73122 significantly inhibited root elongation and disrupted root morphology in a concentration-dependent manner, with the response being saturated at 5 μM, whereas the inactive analogue U73343 was ineffective. The primary root appeared to lose growth directionality accompanied by root waving and formation of curls. Immunolabelling of roots exposed to increasingly higher U73122 concentrations revealed that the normal transverse arrays of cortical microtubules in the elongation zone became progressively more disorganized or depolymerized, with the disorganization appearing within 1 h of incubation. Likewise, actin microfilament arrays also were disrupted. Inhibiting PLC using an alternative inhibitor, neomycin, caused similar disruptions to both cytoskeletal organization and root morphology. In seedlings gravistimulated by rotating the culture plates by 90°, both U73122 and neomycin disrupted the normal gravitropic growth of roots and etiolated hypocotyls. The effects of PLC inhibitors are therefore consistent with the notion that, as with phospholipases A and D, PLC likewise interacts with the cytoskeleton, alters growth morphology, and is involved in gravitropism.
1 Department of Psychology, Columbia University, New York; 2 Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York; and 3 Department of ...Psychology, Barnard College, New York, New York
Submitted 3 November 2008
; accepted in final form 19 December 2008
As central nervous system residents, mast cells contain many cytokines and are localized primarily near large blood vessels in the diencephalon and within the leptomeninges, making them candidates for immune to neural "cross talk." Using mast cell-deficient Kit W-sh/W-sh mice, we assessed the role of these cells in the thermoregulatory component of the immune response to lipopolysaccharide (LPS). Kit W-sh/W-sh and wild-type (WT) mice differed in several respects in response to injection of a high dose of LPS (1 mg/kg ip). Core temperature (T c ) of WT mice decreased by 3°C, whereas Kit W-sh/W-sh mice did not become hypothermic but instead exhibited pronounced low-frequency T c oscillations around their baseline temperature. In addition, Kit W-sh/W-sh mice had lower levels of whole brain TNF- but no differences in IL-1β, IL-6, IFN- , or histamine compared with WT mice following injection of the high dose of LPS, consistent with the role of TNF- in sepsis. Kit W-sh/W-sh mice had increased resistance to LPS, and some survived a dose of LPS that was lethal in littermate controls. In contrast, Kit W-sh/W-sh and WT mice were similar in other aspects, namely, in the hyperthermia following injection of TNF- (1.5 µg icv), reduced nighttime T c and locomotor activity (to 1 mg/kg LPS), response to a low dose of LPS (10 µg/kg ip), and response to subcutaneous turpentine injection. These results indicate that mast cells play a role in the regulation of thermoregulatory responses and survival following sepsis induction and suggest a brain site of action.
tumor necrosis factor- ; interleukins; interferon- ; histamine; mast cell-deficient sash mice; hypothermia
Address for reprint requests and other correspondence: R. Silver, Dept. of Psychology, Columbia Univ., 1190 Amsterdam Ave., 406 Schermerhorn Hall, MC 5501, New York, NY 10027 (e-mail: qr{at}columbia.edu )
Abstract Schizophrenia is one of the most common psychiatric disorders, but despite progress in identifying the genetic factors implicated in its development, the mechanisms underlying its etiology ...and pathogenesis remain poorly understood. Development of mouse models is critical for expanding our understanding of the causes of schizophrenia. However, translation of disease pathology into mouse models has proven to be challenging, primarily due to the complex genetic architecture of schizophrenia and the difficulties in the re-creation of susceptibility alleles in the mouse genome. In this review we highlight current research on models of major susceptibility loci and the information accrued from their analysis. We describe and compare the different approaches that are necessitated by diverse susceptibility alleles, and discuss their advantages and drawbacks. Finally, we discuss emerging mouse models, such as second-generation pathophysiology models based on innovative approaches that are facilitated by the information gathered from the current genetic mouse models. This article is part of a Special Issue entitled: Neuroscience Disease Models.
Molecules, Signaling, and Schizophrenia Kvajo, Mirna; McKellar, Heather; Gogos, Joseph A.
Behavioral Neurobiology of Schizophrenia and Its Treatment,
01/2010, Letnik:
4
Book Chapter, Journal Article
Recenzirano
Schizophrenia is one of the most common psychiatric disorders, but despite some progress in identifying the genetic factors implicated in its development, the molecular mechanisms underlying its ...etiology and pathogenesis remain poorly understood. However, accumulating evidence suggests that regardless of the underlying genetic complexity, the mechanisms of the disease may impact a small number of common signaling pathways. In this review, we discuss the evidence for a role of schizophrenia susceptibility genes in intracellular signaling cascades by focusing on three prominent candidate genes: AKT, PPP3CC (calcineurin), and DISC1. We describe the regulation of a number of signaling cascades by AKT and calcineurin through protein phosphorylation and dephosphorylation, and the recently uncovered functions of DISC1 in cAMP and GSK3β signaling. In addition, we present independent evidence for the involvement of their downstream signaling pathways in schizophrenia. Finally, we discuss evidence supporting an impact of these susceptibility genes on common intracellular signaling pathways and the convergence of their effects on neuronal processes implicated in schizophrenia.
Female rats modulate the number and interval between the intromissions the female receives during mating. This patterned vaginocervical stimulation (VCS) is critical for triggering long-term changes ...in prolactin (PRL) secretion necessary for pregnancy or pseudopregnancy (P/PSP). Previous work has shown that NMDA receptor activation in the posterodorsal medial amygdala (MEApd) is required at the time of mating for VCS to induce the twice-daily PRL surges characteristic of P/PSP. The current studies examined whether patterned activation of glutamate receptors within the MEApd induces P/PSP. In anesthetized, cycling females, three 0.27 microg NMDA infusions given at 30 min intervals into the MEApd initiated P/PSP, whereas a single NMDA infusion of the same total dose (0.8 microg) had no effect. In conscious, freely behaving females, three infusions of an excitatory amino acid (EAA) mixture applied at the same interval were more effective in initiating P/PSP and nocturnal PRL surges than were single infusions at the same or higher concentrations. Infusion intervals of 5 and 60 min as well as continuous 1 h infusion did not induce P/PSP. Finally, a synergistic effect was observed between EAA and mating stimulation, because a subthreshold EAA infusion combined with subthreshold numbers of intromissions induced P/PSP. These results demonstrate that repeated, properly spaced, temporally discreet periods of glutamate receptor activation within the MEApd, which mimic mating stimulation, encode for P/PSP. Such findings suggest that single intromissions normally release individually subthreshold quanta of glutamate within the MEApd that summate to induce P/PSP.
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