Neuronal Pentraxins Mediate Synaptic Refinement in the Developing Visual System

Neuronal activity regulated pentraxin (Narp) is a secreted neuronal product which clusters AMPA receptors and regulates excitatory synaptogenesis. Although Narp is selectively enriched in brain, its role in behavior is not known. As Narp is expressed prominently in limbic regions, we examined whether Narp deletion affects performance on tasks used to assess motivational consequences of foodrewarded learning. Narp knock-out (KO) mice were unimpaired in learning simple pavlovian discriminations, instrumental lever pressing, and in acquisition of at least two aspects of pavlovian incentive learning, conditioned reinforcement and pavlovian-instrumental transfer. In contrast, Narp deletion resulted in a substantial deficit in the ability to use specific outcome expectancies to modulate instrumental performance in a devaluation task. In this task, mice were trained to respond on two levers for two different rewards. After training, mice were prefed with one of the two rewards, devaluing it. Responding on both levers was then assessed in extinction. Whereas control mice showed a significant preference in responding on the lever associated with the nondevalued reward, Narp KO mice responded equally on both levers, failing to suppress responding on the lever associated with the devalued reward. Both groups consumed more of the nondevalued reward in a subsequent choice test, indicating Narp KO mice could distinguish between the rewards themselves. These data suggest Narp has a selective role in processing sensory-specific information necessary for appropriate devaluation performance, but not in general motivational effects of reward-predictive cues on performance.

Section: Discussionmentioning

confidence: 56%

A Selective Role for Neuronal Activity Regulated Pentraxin in the Processing of Sensory-Specific Incentive Value

Johnson¹,

Crombag²,

Takamiya³

et al. 2007

“…The finding that silencing the expression of NP1 prevents the decrease in synaptophysin levels evoked by A␤ suggests that NP1 contributes to the synaptic damage evoked by A␤ and provides a molecular basis for this A␤-induced depression of synaptic transmission. The interpretation that NP1 regulates synaptogenesis and synaptophysin levels in response to changes in neuronal activity is supported by recent studies showing that NP1 knock-out mice exhibit defects in the segregation of eye-specific retinal ganglion cell projections to the dorsal lateral geniculate nucleus, a process that involves activity-dependent synapse formation (Bjartmar et al, 2006). Moreover, NP1 has been proposed to regulate synaptogenesis by forming pentraxin heterocomplexes with NP2 (Xu et al, 2003).…”

Section: Discussionmentioning

confidence: 95%

Neuronal Pentraxin 1 Contributes to the Neuronal Damage Evoked by Amyloid-β and Is Overexpressed in Dystrophic Neurites in Alzheimer's Brain

Abad¹,

Enguita²,

DeGregorio-Rocasolano³

et al. 2006

Accumulation of amyloid-␤ (A␤) is thought to play a central role in the progressive loss of synapses, the neurite damage, and the neuronal death that are characteristic in brains affected by Alzheimer's disease. However, the mechanisms through which A␤ produces such neurotoxicity remain unclear. Because A␤ depresses synaptic activity, we investigated whether the neurotoxicity of A␤ depends on the expression of NP1, a protein involved in excitatory synapse remodeling that has recently been shown to mediate neuronal death induced by reduction in neuronal activity in mature neurons. We found that treatment of cortical neurons in culture with A␤ produces a marked increase in NP1 protein that precedes apoptotic neurotoxicity. Silencing NP1 gene expression by RNA interference (short hairpin RNA for RNA interference) prevents the loss of synapses, the reduction in neurite outgrowth, and the apoptosis evoked by A␤. Transgene overexpression of NP1 reproduced these neurotoxic effects of A␤. Moreover, we found that NP1 was increased in dystrophic neurites of brains from patients with sporadic late-onset Alzheimer's disease. Dual immunohistochemistry for NP1 and tau showed that NP1 colocalizes with tau deposits in dystrophic neurites. Furthermore, NP1 colocalized with SNAP-25 (synaptosomal-associated protein of 25 kDa) in the majority of dystrophic neurites surrounding amyloid deposits. NP1 was also increased in cell processes surrounding amyloid plaques in the cerebral cortex and hippocampus of APP/PS1 (mutant amyloid precursor protein/presenilin 1) transgenic mice. These findings show that NP1 is a key factor for the synapse loss, the neurite damage, and the apoptotic neuronal death evoked by A␤ and indicate that A␤ contributes to the pathology of Alzheimer's disease by regulating NP1 expression.

“…Nptx2 and other neuronal pentraxins are proposed to regulate activity-dependent synaptic plasticity via AMPA receptor clustering in hippocampal spines based primarily on in vitro studies; these functions suggest that neuronal pentraxins participate in learning and memory (O'Brien et al, 1999). However, deleting all three members of this family in mice resulted in a mild impairment of retinal activity, whereas hippocampal long-term potentiation and long-term depression appeared normal (Bjartmar et al, 2006). In the hypothalamus, others have suggested that lateral hypothalamic neuropeptides, hypocretin and MCH, use neuronal pentraxins to influence synapse formation of target neurons (Reti et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

The Neonatal Ventromedial Hypothalamus Transcriptome Reveals Novel Markers with Spatially Distinct Patterning

Kurrasch¹,

Cheung²,

Lee³

et al. 2007

155

151

The ventromedial hypothalamus (VMH) is a distinct morphological nucleus involved in feeding, fear, thermoregulation, and sexual activity. It is essentially unknown how VMH circuits underlying these innate responses develop, in part because the VMH remains poorly defined at a cellular and molecular level. Specifically, there is a paucity of cell-type-specific genetic markers with which to identify neuronal subgroups and manipulate development and signaling in vivo. Using gene profiling, we now identify ϳ200 genes highly enriched in neonatal (postnatal day 0) mouse VMH tissue. Analyses of these VMH markers by real or virtual (Allen Brain Atlas; http:// www.brain-map.org) experiments revealed distinct regional patterning within the newly formed VMH. Top neonatal markers include transcriptional regulators such as Vgll2, SF-1, Sox14, Satb2, Fezf1, Dax1, Nkx2-2, and COUP-TFII, but interestingly, the highest expressed VMH transcript, the transcriptional coregulator Vgll2, is completely absent in older animals. Collective results from zebrafish knockdown experiments and from cellular studies suggest that a subset of these VMH markers will be important for hypothalamic development and will be downstream of SF-1, a critical factor for normal VMH differentiation. We show that at least one VMH marker, the AT-rich binding protein Satb2, was responsive to the loss of leptin signaling (Lep ob/ob ) at postnatal day 0 but not in the adult, suggesting that some VMH transcriptional programs might be influenced by fetal or early postnatal environments. Our study describing this comprehensive "VMH transcriptome" provides a novel molecular toolkit to probe further the genetic basis of innate neuroendocrine behavioral responses.