Biomedical subjects

Leszek Kaczmarek

Publications and source records attributed to Leszek Kaczmarek.

29 records · Page 2Linked to original sources

PubMed2004

A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK?

Zif268 is a transcription regulatory protein, the product of an immediate early gene. Zif268 was originally described as inducible in cell cultures; however, it was later shown to be activated by a variety of stimuli, including ongoing synaptic activity in the adult brain. Recently, mice with experimentally mutated zif268 gene have been obtained and employed in neurobiological research. In this review we present a critical overview of Zif268 expression patterns in the naive brain and following neuronal stimulation as well as functional data with Zif268 mutants. In conclusion, we suggest that Zif268 expression and function should be considered in a context of neuronal activity that is tightly linked to neuronal plasticity.

Animals↗

PubMed2003

Inducible cAMP early repressor, an endogenous antagonist of cAMP responsive element-binding protein, evokes neuronal apoptosis in vitro.

Active CREB (cAMP responsive element-binding protein) transcription factor is crucial for neuronal survival. Several members of the CREM/ICER (cAMP responsive element modulator/inducible cAMP early repressor) protein family may act as endogenous CREB antagonists. However, their involvement in a process of programmed cell death remains unexplored. Here we report that ICER may play such a role in neuronal apoptosis because it is upregulated in apoptotic neurons in vitro, and overexpression of ICER, delivered in adenoviral vector, evokes programmed cell death of three different kinds of cultured neurons, namely those derived from hippocampal dentate gyrus, cerebral cortex, and superior cervical ganglion. Reporter gene assay with a promoter containing a CREB-responsive sequence revealed a decrease in both basal and induced CRE-dependent gene expression in neurons overexpressing ICER. Finally, the level of expression of the anti-apoptotic protein Bcl-2, a well known CREB target, was markedly diminished in ICER-treated neurons. We suggest that the naturally occurring CREB functional antagonist ICER may have a specific function in programmed cell death of neurons, probably by silencing the expression of anti-apoptotic genes.

Adenoviridae↗

PubMed2003

Inducible cAMP early repressor (ICER) in the nervous system--a transcriptional regulator of neuronal plasticity and programmed cell death.

The acronym ICER (inducible cAMP early repressor) refers to a group of four proteins produced from the CREM/ICER gene due to use of an internal promoter (P2) placed in an intron of the CREM (cAMP responsive element modulator) gene. The ICER proteins contain DNA binding/leucine zipper domains that make them endogenous inhibitors of transcription driven by CREB (cAMP responsive element binding protein) and its cognates, CREM and ATF-1 (activating transcription factor-1). ICER expression is inducible in the brain and in neuronal culture by a variety of stimuli. As a CREB antagonist, ICER appears to be of pivotal importance in neuronal plasticity and programmed cell death.

Animals↗

PubMed2002

Matrix metalloproteinases in the adult brain physiology: a link between c-Fos, AP-1 and remodeling of neuronal connections?

Matrix metalloproteinases (MMPs), together with their endogenous inhibitors (TIMPs) form an enzymatic system that plays an important role in a variety of physiological and pathological conditions. These proteins are also expressed in the brain, especially under pathological conditions, in which glia as well as invading inflammatory cells provide the major source of the MMP activity. Surprisingly little is known about the MMP function(s) in adult neuronal physiology. This review describes available data on this topic, which is presented in a context of knowledge about the MMP/TIMP system in other organs as well as in brain disorders. An analysis of the MMP and TIMP expression patterns in the brain, along with a consideration of their regulatory mechanisms and substrates, leads to the proposal of possible roles of the MMP system in the brain. This analysis suggests that MMPs may play an important role in the neuronal physiology, especially in neuronal plasticity, including their direct participation in the remodeling of synaptic connections-a mechanism pivotal for learning and memory.

Animals↗

PubMed2002

Environmental manipulation differentially alters c-Fos expression in amygdaloid nuclei following aversive conditioning.

This study analyzes the impact of environmental complexity in adult rats on their emotional behavior and c-Fos expression (a transcription factor protein implicated in neuronal plasticity) in various subdivisions of amygdala, as well as selected parts of the thalamus and hypothalamus. The animals were housed for 60 days in either enriched or impoverished conditions and then one group of rats was tested in an open field test, and a second group of rats was treated to footshock-motivated aversive training. Two and 24 h later, the animals from the second group, along with the appropriate controls, were sacrificed and their brains were used for the immunocytochemical analysis of c-Fos levels. We found that this long-term environmental manipulation exerts significant effects on animals' emotionality and this behavioral difference is accompanied by the differential c-Fos activation (at 2 h after the aversive training) in the amygdala, a brain structure believed to subserve emotional reactions. On the other hand, no difference was found in c-Fos expression between both groups of animals in the thalamus and hypothalamus. At 24 h after the training, c-Fos levels were down to the values observed in naive rats that did not differentiate between enriched versus impoverished breeding conditions. These results may help to explain differential emotional aspects of behavior that arise following differential housing conditions of adult animals.

Amygdala↗

PubMed2002

Differential response of two subdivisions of lateral amygdala to aversive conditioning as revealed by c-Fos and P-ERK mapping.

Rats were subjected to two aversive learning protocols: either classical (fear conditioning) or instrumental (two-way active avoidance training). Next, immunocytochemical mapping of phosphorylated extracellular signal-regulated kinase (P-ERK) and c-Fos transcription factor protein was performed, and the expression pattern of both markers within the dorsal nucleus of lateral amygdala (LaD) was analyzed. As immunocytochemical studies revealed, aversive training induced ERK phosphorylation and c-Fos expression specifically in ventral but not dorsal tip of LaD. These data show for the first time molecular distinction between subdivisions of LaD as well as they also strengthen the idea of Repa that the neurons in the ventral tip of LaD are involved in storage of long-lasting changes associated with formation of fear memories.

Amygdala↗

PubMed2002

Estrogen receptor beta. Potential functional significance of a variety of mRNA isoforms.

Recent cloning of estrogen receptor beta (ERbeta) was followed by the discovery of a variety of its isoforms. This review describes the complexity of ERbeta mRNAs in various species for which most data have been gathered so far. The most surprising finding is the great variation in isoform structure among various mammalian species. This may reflect either the fact that only a very limited number of isoforms have been described so far or between-species specificity, especially as common elements in closely related species could still be noted. Isoform variations, as detected mainly at the mRNA sequence level, should result in profound functional differences at the level of proteins as already shown in selected cases. Thus, it is proposed that the diversity of ERbeta isoforms implies a functional role of this phenomenon in cellular physiology and pathology of estrogen response.

Animals↗

PubMed2002

Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus.

Neurons of adult brain are able to remodel their synaptic connections in response to various stimuli. Modifications of the peridendritic environment, including the extracellular matrix, are likely to play a role during synapse remodeling. Proteolytic disassembly of ECM is a complex process using the regulated actions of specific extracellular proteinases. One of best-characterized families of matrix-modifying enzymes is the matrix metalloproteinase (MMP) family. Here, we describe changes in the expression and function of two well known MMPs, MMP-9 and MMP-2, in adult rat brain before and after systemic administration of the glutamate receptor agonist kainate. Kainate application results in enhanced synaptic transmission and seizures followed by selective tissue remodeling, primarily in hippocampal dentate gyrus. MMP-9 but not MMP-2 was highly expressed by neurons in normal adult rat brain. MMP-9 protein was localized in neuronal cell bodies and dendrites. Kainate upregulated the level of MMP-9 mRNA and protein within hours after drug administration. This was followed several hours later by MMP-9 enzymatic activation. Within hippocampus, MMP-9 mRNA and activity were increased selectively in dentate gyrus, including its dendritic layer. In addition, MMP-9 mRNA levels decreased in areas undergoing neuronal cell loss. This unique spatiotemporal pattern of MMP-9 expression suggests its involvement in activity-dependent remodeling of dendritic architecture with possible effects on synaptic physiology.

Animals↗

PubMed2002

Gelatinase B and TIMP-1 are regulated in a cell- and time-dependent manner in association with neuronal death and glial reactivity after global forebrain ischemia.

Matrix metalloproteinases (MMPs) belong to a large family of endopeptidases that regulate the pericellular environment through the cleavage of protein components of the extracellular matrix, membrane receptors and cytokines. MMP activity is controlled by the multifunctional tissue inhibitors of metalloproteinases (TIMPs). Proteases and their inhibitors are critically involved in developmental and pathological processes in numerous organs, including the brain. Global transient cerebral ischemia induces selective delayed neuronal death and neuroinflammation. We compared, in discrete vulnerable and resistant areas of the ischemic rat hippocampus, the kinetics and cellular distribution of gelatinase B and its principal inhibitor TIMP-1 and we assessed by in situ zymography, the net gelatinolytic activity at the cellular level. We show that gelatinases are expressed and active in neurons, suggesting that MMPs play a role in maintaining neural homeostasis. In the ischemic rat brain, expression and activity of gelatinase B, and expression of TIMP-1 are altered in a time-, region- and cell-dependent manner. Gelatinase B is induced first in reactive microglia and subsequently in reactive astrocytes. In situ, increases in gelatinase activity accompanied the progression of neuronal death and glial reactivity. Our results suggest that MMPs and TIMPs are involved in cell viability and tissue remodelling in the ischemic brain, and reinforces the idea that the MMP/TIMP system contributes both to neuronal demise and tissue repair in the context of glial reactivity.

Animals↗

PubMedDate not supplied

hCMV and Tet promoters for inducible gene expression in rat neurons in vitro and in vivo.

To advance our understanding of the central nervous system, there is a need for refined approaches to control gene expression in neuronal culture as well as in the brain in vivo. In this study, we have applied a doxycycline-responsive Tet system to obtain a tightly controlled gene expression in neurons. In the absence of doxycycline, the Tet promoter-driven transgene expression was blocked by Tet transrepressor (tTR). Expression was doxycycline activated with the aid of a reverse Tet transactivator (rtTA). Application of both tTR and rtTA resulted in a much greater inducibility, as compared to rtTA alone, mainly due to a decreased basal level of expression. Such effects were observed when tTR and rtTA were driven in cultured neurons by the alpha CaMKII promoter. However, introduction of the human CMV major immediate-early promoter resulted only in a mediocre neuronal gene expression, unless the cells were treated, either in culture or in vivo, with depolarizing concentrations of KCl. Thus, in the present report, we have examined hCMV and Tet promoter inducibility in neurons to produce an important improvement in the functioning of the Tet system.

Animals↗

PubMedDate not supplied

Complex effects of NMDA receptor antagonist APV in the basolateral amygdala on acquisition of two-way avoidance reaction and long-term fear memory.

Although much has been learned about the role of the amygdala in Pavlovian fear conditioning, relatively little is known about an involvement of this structure in more complex aversive learning, such as acquisition of an active avoidance reaction. In the present study, rats with a pretraining injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoic acid (APV), into the basolateral amygdala (BLA) were found to be impaired in two-way active avoidance learning. During multitrial training in a shuttle box, the APV-injected rats were not different from the controls in sensitivity to shock or in acquisition of freezing to contextual cues. However, APV injection led to impaired retention of contextual fear when tested 48 h later, along with an attenuation of c-Fos expression in the amygdala. These results are consistent with the role of NMDA receptors of the BLA in long-term memory of fear, previously documented in Pavlovian conditioning paradigms. The APV-induced impairment in the active avoidance learning coincided with deficits in directionality of the escape reaction and in attention to conditioned stimuli. These data indicate that normal functioning of NMDA receptors in the basolateral amygdala is required during acquisition of adaptive instrumental responses in a shuttle box but is not necessary for acquisition of short-term contextual fear in this situation.

2-Amino-5-phosphonovalerate↗