Select cognitive deficits in Vasoactive Intestinal Peptide deficient mice

Research articl

Expression of the circadian clock gene Period2 in the hippocampus: possible implications for synaptic plasticity and learned behaviour

Genes responsible for generating circadian oscillations are expressed in a variety of brain regions not typically associated with circadian timing. The functions of this clock gene expression are largely unknown, and in the present study we sought to explore the role of the Per2 (Period 2) gene in hippocampal physiology and learned behaviour. We found that PER2 protein is highly expressed in hippocampal pyramidal cell layers and that the expression of both protein and mRNA varies with a circadian rhythm. The peaks of these rhythms occur in the late night or early morning and are almost 180° out-of-phase with the expression rhythms measured from the suprachiasmatic nucleus of the same animals. The rhythms in Per2 expression are autonomous as they are present in isolated hippocampal slices maintained in culture. Physiologically, Per2-mutant mice exhibit abnormal long-term potentiation. The underlying mechanism is suggested by the finding that levels of phosphorylated cAMP-response-element-binding protein, but not phosphorylated extracellular-signal-regulated kinase, are reduced in hippocampal tissue from mutant mice. Finally, Per2-mutant mice exhibit deficits in the recall of trace, but not cued, fear conditioning. Taken together, these results provide evidence that hippocampal cells contain an autonomous circadian clock. Furthermore, the clock gene Per2 may play a role in the regulation of long-term potentiation and in the recall of some forms of learned behaviour

DNA binding activity of the fetal Alz-50 clone 1 (FAC1) protein is enhanced by phosphorylation

Fetal Alz-50 clone 1 (FAC1) is a novel DNA binding protein with altered expression and subcellular localization during neuronal development and degeneration. FAC1 localizes to the cell body and neurites in undifferentiated neurons during development and in degenerating neurons during Alzheimer\u27s disease progression. In the normal adult brain FAC1 is present predominantly in the nucleus of cortical neurons. When in the nucleus FAC1 has been shown to repress transcription by binding a specific DNA sequence. In the present study we demonstrate that the affinity of FAC1 for the identified DNA sequence is dramatically enhanced when FAC1 is phosphorylated. Phosphatase treatment of neuroblastoma nuclear extracts reduces FAC1 DNA binding affinity. Finally, inhibition of cellular serine/threonine phosphatases results in increased FAC1 DNA binding activity. These data suggest that FAC1 DNA binding activity is dependent upon and regulated by phosphorylation signals in the cell

Fetal Alz-50 clone 1, a novel zinc finger protein, binds a specific DNA sequence and acts as a transcriptional regulator

Fetal Alz-50 clone 1 (FAC1) is a novel, developmentally regulated gene that exhibits changes in protein expression and subcellular localization during neuronal development and neurodegeneration. To understand the functional implications of altered subcellular localization, we have established a normal cellular function of FAC1. The FAC1 amino acid sequence contains regional homology to transcriptional regulators. Using the polymerase chain reaction-assisted binding site selection assay, we have identified a DNA sequence recognized by recombinant FAC1. Mutation of any 2 adjacent base pairs in the identified binding site dramatically reduced the binding preference of FAC1, demonstrating that the binding is specific for the identified site. Nuclear extracts from neural and non-neural cell lines contained a DNA-binding activity with similar specificity and nucleotide requirements as the recombinant FAC1 protein. This DNA-binding activity can be attributed to FAC1 since it is dependent upon the presence of FAC1 and behaves identically on a nondenaturing polyacrylamide gel as transiently transfected FAC1. In NIH3T3 cells, luciferase reporter plasmids containing the identified binding site (CACAACAC) were repressed by cotransfected FAC1 whether the binding site was proximal or distal to the transcription initiation site. This study indicates that FAC1 is a DNA-binding protein that functions as a transcription factor when localized to the nucleus

Select cognitive deficits in vasoactive intestinal peptide deficient mice.

BackgroundThe neuropeptide vasoactive intestinal peptide (VIP) is widely distributed in the adult central nervous system where this peptide functions to regulate synaptic transmission and neural excitability. The expression of VIP and its receptors in brain regions implicated in learning and memory functions, including the hippocampus, cortex, and amygdala, raise the possibility that this peptide may function to modulate learned behaviors. Among other actions, the loss of VIP has a profound effect on circadian timing and may specifically influence the temporal regulation of learning and memory functions.ResultsIn the present study, we utilized transgenic VIP-deficient mice and the contextual fear conditioning paradigm to explore the impact of the loss of this peptide on a learned behavior. We found that VIP-deficient mice exhibited normal shock-evoked freezing behavior and increases in corticosterone. Similarly, these mutant mice exhibited no deficits in the acquisition or recall of the fear-conditioned behavior when tested 24-hours after training. The VIP-deficient mice exhibited a significant reduction in recall when tested 48-hours or longer after training. Surprisingly, we found that the VIP-deficient mice continued to express circadian rhythms in the recall of the training even in those individual mice whose wheel running wheel activity was arrhythmic. One mechanistic explanation is suggested by the finding that daily rhythms in the expression of the clock gene Period2 continue in the hippocampus of VIP-deficient mice.ConclusionTogether these data suggest that the neuropeptide VIP regulates the recall of at least one learned behavior but does not impact the circadian regulation of this behavior

Expression of the circadian clock gene Period2 in the hippocampus: possible implications for synaptic plasticity and learned behaviour.

Genes responsible for generating circadian oscillations are expressed in a variety of brain regions not typically associated with circadian timing. The functions of this clock gene expression are largely unknown, and in the present study we sought to explore the role of the Per2 (Period 2) gene in hippocampal physiology and learned behaviour. We found that PER2 protein is highly expressed in hippocampal pyramidal cell layers and that the expression of both protein and mRNA varies with a circadian rhythm. The peaks of these rhythms occur in the late night or early morning and are almost 180° out-of-phase with the expression rhythms measured from the suprachiasmatic nucleus of the same animals. The rhythms in Per2 expression are autonomous as they are present in isolated hippocampal slices maintained in culture. Physiologically, Per2-mutant mice exhibit abnormal long-term potentiation. The underlying mechanism is suggested by the finding that levels of phosphorylated cAMP-response-element-binding protein, but not phosphorylated extracellular-signal-regulated kinase, are reduced in hippocampal tissue from mutant mice. Finally, Per2-mutant mice exhibit deficits in the recall of trace, but not cued, fear conditioning. Taken together, these results provide evidence that hippocampal cells contain an autonomous circadian clock. Furthermore, the clock gene Per2 may play a role in the regulation of long-term potentiation and in the recall of some forms of learned behaviour