[Functional Responses to the Chronic Activation of 5-HT1A Receptors in Mice with Genetic Predisposition to Catalepsy].

The effects of chronic 5-HT1A receptor activation on the behavior, functional activity of 5-HT1A receptors, and expression of key genes of the brain 5-HT system were studied in mice of the catalepsy-prone CBA strain and the catalepsy-resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensiti-zation of 5-HT1A receptors in both strains. Pretreatment with the 5-HT7 receptor agonist SB 269970 did not affect the hypothermic response to the acute administration of 8-OH-DPAT, which suggests an independent functional response of 5-HT1A receptors. The treatment did not induce any changes in the behavior in the open field paradigm in CBA mice, but significantly increased the total path, the time spent in the center, and the number of rearings in C57BL/6 mice, which indicates the enhancement of locomotor and exploratory activity in C57BL/6 mice. The chronic activation of 5-HT1A receptor downregulated 5-HT1A gene expression, as well as the expression of the gene that encodes tryptophan hydroxylase 2, a key enzyme of 5-HT biosynthesis, in the midbrain and the expression of the gene that encodes the 5-HT2A receptor in the frontal cortex of CBA, but not C57BL/6 mice. The obtained data provide a new evidence on the receptor-gene cross talk in the brain 5-HT system that may underlie the loss of pharmacological efficacy of 5-HT1A receptor agonists. In turn, the loss of the behavioral response and compensatory alterations in key genes of the brain 5-HT system in CBA mice suggests that catalepsy-prone and -resistant genotypes demonstrate different sensibility to the effects of drugs.

Neurotrophic Factors (BDNF and GDNF) and the Serotonergic System of the Brain.

Neurotrophic factors play a key role in development, differentiation, synaptogenesis, and survival of neurons in the brain as well as in the process of their adaptation to external influences. The serotonergic (5-HT) system is another major factor in the development and neuroplasticity of the brain. In the present review, the results of our own research as well as data provided in the corresponding literature on the interaction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) with the 5-HT-system of the brain are considered. Attention is given to comparison of BDNF and GDNF, the latter belonging to a different family of neurotrophic factors and being mainly considered as a dopaminergic system controller. Data cited in this review show that: (i) BDNF and GDNF interact with the 5-HT-system of the brain through feedback mechanisms engaged in autoregulation of the complex involving 5-HT-system and neurotrophic factors; (ii) GDNF, as well as BDNF, stimulates the growth of 5-HT neurons and affects the expression of key genes of the brain 5-HT-system - those coding tryptophan hydroxylase-2 and 5-HT1A and 5-HT2A receptors. In turn, 5-HT affects the expression of genes that control BDNF and GDNF in brain structures; (iii) the difference between BDNF and GDNF is manifested in different levels and relative distribution of expression of these factors in brain structures (BDNF expression is highest in hippocampus and cortex, GDNF expression in the striatum), in varying reaction of 5-HT2A receptors on BDNF and GDNF administration, and in different effects on certain types of behavior.

[5-HT1A/5-HT7 receptor interplay: Chronic activation of 5-HT7 receptors decreases the functional activity of 5-HT1A receptor and its сontent in the mouse brain].

Serotonin receptors 5-HT1A and 5-HT7 are involved in the development of various psychopathologies. Some data indicate that there is an interplay between 5-HT1A 5-HT7 receptors that could be implicated in the regulation of their function. This work analyzed the effects of chronic 5-HT7 activation on the functional activity of 5-HT7 and 5-HT1A receptors, on the corresponding protein levels, and on the expression of genes encoding 5-HT7 and 5-HT1A receptors in the mouse brain. Chronic administration of the 5-HT7 selective agonist LP44 (20.5 nmol, i.c.v., 14 days) produced considerable desensitization of both 5-HT7 and 5-HT1A receptors. In LP44-treated mice, the hypothermic responses mediated by both 5-HT7 and 5-HT1A receptors were attenuated. Moreover, the levels of 5-HT1A receptor protein in the midbrain and the frontal cortex of LP44-treated mice were significantly decreased. However, the brain levels of 5-HT7 receptor protein did not differ between LP44-treated and control mice. Chronic LP44 treatment did not alter the expression of the 5-HT7 and 5-HT1A receptor genes in all investigated brain structure. These data suggest that 5-HT7 receptors participate in the posttranscriptional regulation of the 5-HT1A receptors functioning.

[The Effects of Chronic Alcoholization on the Expression of Brain-Derived Neurotrophic Factor and Its Receptors in the Brains of Mice Genetically Predisposed to Depressive-Like Behavior].

Brain-derived neurotropic factor (BDNF) plays an important role in mechanisms of depression. Precursor protein of this factor (proBDNF) can initiate apoptosis in the brain, while the mature form of BDNF is involved in neurogenesis. It is known that chronic alcoholization leads to the activation of apoptotic processes, neurodegeneration, brain injury, and cognitive dysfunction. In this work, we have studied the influence of long-term ethanol exposure on the proBDNF and BDNF protein levels, as well as on the expression of genes that encode these proteins in the brain structures of ASC mice with genetic predisposition to depressive-like behavior and in mice from parental nondepressive CBA strain. It was shown that chronic alcoholization results in a reduction of the BDNF level in the hippocampus and an increase in the amount of TrkB and p75 receptors in the frontal cortex of nondepressive CBA mice. At the same time, the long-term alcoholization of depressive ASC mice results in an increase of the proBDNF level in the frontal cortex and a reduction in the p75 protein level in the hippocampus. It has also been shown that, in depressive ASC mice, proBDNF and BDNF levels are significantly lower in the hippocampus and the frontal cortex compared with nondepressive CBA strain. However, no significant differences in the expression of genes encoding the studied proteins were observed. Thus, changes in the expression patterns of proBDNF, BDNF, and their receptors under the influence of alcoholization in the depressive ASC strain and nondepressive CBA strain mice are different.

[Expression of apoptosis genes in the brain of rats with genetically defined fear-induced aggression].

The programmed cell death (or apoptosis) plays an important role both in developing and mature brains. Multiple data indicate the involvement of processes of apoptosis in mechanisms of different psychopathologies. At the same time, nothing is known about the role of apoptosis in the regulation of genetically defined aggression. In the present work, the expression of the genes that encode main pro- and antiapoptotic BAX and BCL-XL proteins, as well as caspase 3 (the main effector of apoptosis), in different brain structures of rats that were selected on a high aggression towards human (or its absence) was studied. A significant increase in the expression of the gene encoding caspase 3 was detected in the hypothalamus. This was accompanied by a significant decrease in the expression of proapoptotic Bax gene in the hippocampus and increase in mRNA level of antiapoptotic Bcl-xl gene in the raphe nuclei area of midbrain in highly aggressive rats. An increase in the ratio Bcl-xl: Bax was found in the midbrain and amygdala; a trend towards an increase in the ratio was also found in hippocampus of aggressive animals compared to tame animals. Thus, we demonstrated that genetically defined fear-induced aggression is associated with significant changes in the genetic control of apoptosis in the brain. It is assumed that an increase in the Bcl-xl gene expression (accompanied by a decrease in the Bax gene expression) can indicate an increase in the threshold of neuronal apoptosis in highly aggressive rats.

[Influence of chronic alcohol treatment on the expression of the Bdnf, Bax, Bcl-xL, and CASP3 genes in the mouse brain: Role of the C1473G polymorphism in the gene encoding tryptophan hydroxylase 2].

Tryptophan hydroxylase 2 (Tph-2) is the key enzyme in serotonin biosynthesis. Serotonin is one of the main neurotransmitters involved in the regulation of various physiological functions and behavior patterns. The influence of chronic ethanol consumption on the expression of the Bdnf, Bax, Bcl-xL, and CASP3 genes was studied in the brain structures of B6-1473C (C/C) and B6-1473G (G/G) mice that had been obtained on the base of the C57BL/6 strain. The strains differed in the genotype for the C1473G single nucleotide polymorphism in the Tph-2 gene and in Tph-2 enzyme activity. It was found that chronic alcohol treatment led to a significant increase in the expression of the Bdnf gene in the midbrain of B6-1473G mice, but not in B6-1473С. Chronic alcohol treatment considerably decreased the expression of the ultimate brain apoptosis effector, caspase 3, in the frontal cortex, but increased it in the hippocampus of B6-1473G mice. At the same time, chronic ethanol administration reduced the level of the antiapoptotic Bcl-xL mRNA in the midbrain of B6-1473C mice. Thus, the C1473G polymorphism in the Tph-2 gene considerably influenced the changes in the expression patterns of genes involved in the regulation of neurogenesis and neural apoptosis induced by chronic ethanol treatment.

Effect of microgravity on glial cell line-derived neurotrophic factor and cerebral dopamine neurotrophic factor gene expression in the mouse brain.

UNLABELLED: Mice were exposed to 1 month of space flight on the Russian biosatellite BION-M1 to determine its effect on the expression of genes involved in the maintenance of the mouse brain dopamine system. The current article focuses on the genes encoding glial cell line-derived neurotrophic factor (GDNF) and cerebral dopamine neurotrophic factor (CDNF). Space flight reduced expression of the GDNF gene in the striatum and hypothalamus but increased it in the frontal cortex and raphe nuclei area. At the same time, actual space flight reduced expression of the gene encoding CDNF in the substantia nigra but increased it in the raphe nuclei area. To separate the effects of space flight from environmental stress contribution, we analyzed expression of the investigated genes in mice housed for 1 month on Earth in the same shuttle cabins that were used for space flight and in mice of the vivarium control group. Shuttle cabin housing failed to alter the expression of the GDNF and CDNF genes in the brain structures investigated. Thus, actual long-term space flight produced dysregulation in genetic control of GDNF and CDNF genes. These changes may be related to downregulation of the dopamine system after space flight, which we have shown earlier. © 2015 Wiley Periodicals, Inc. SIGNIFICANCE: Our results provide the first evidence of microgravity effects on expression of the GDNF and CDNF neurotrophic factor genes. A considerable decrease in mRNA level of GDNF and CDNF in the nigrostriatal dopamine system was found. Because both GDNF and CDNF play a significant role in maintenance and survival of brain dopaminergic neurons, we can assume that this dysregulation in genetic control of GDNF and CDNF genes in substantia nigra could be among the reasons for the deleterious effects of space flight on the dopamine system.

[On the Functional Cross-Talk between Brain 5-HT1A and 5-HT2A Receptors].

We have found that activation of 5-HT1A receptor with 8-OH-DPAT (0.1, 0.5 and 1.0 mg/kg, i. p.) considerably and dose-dependently reduced the number of 5-HT2A receptor-mediated head-twitches, whereas 5-HT1A receptor blockade with WAY-100635 (0.5 and 1.0 mg/kg, i. p.), on the contrary, pro- duced significant enhancement of this 5-HT2A receptor functional response. At the same time 5-HTA receptor activation with DOI (0.5 and 1.0 mg/kg, i. p.) abolished the 5-HT1A receptor-mediated hypothermic reaction, whereas 5-HT2A receptor blockade with ketanserin (1.0 and 2.0 mg/kg, i. p.) increased this 5-HT1A receptor functional response. Moreover, we revealed that 5-HT2A receptor antagonist ketanserin (1.0 and 2.0 mg/kg, i. p.; or 20 and 40 nmol, i. c. v.) produced the considerable dose-dependent hypothermia. This ketanserin-induced (40 nmol, i. c. v.) hypothermic reaction was significantly attenuated by pretreatment with 5-HT1A receptor antagonist WAY-100635 (1.0 mg/kg, i. p.), indicating that 5-HT2A receptor-related hypothermic response is mediated, at least partially, via activation of 5-HT1A receptors. The obtained data indicate that 5-HTA and 5-HT2A receptors are able to modulate each other functional activity by means of bilateral functional cross-talk.

[The effect of central administration of the neurotrophic factors BDNF and GDNF on the functional activity and expression of the serotonin 5-HT2A receptors in mice genetically predisposed to depressive-like behavior].

Brain serotonin (5-HT) system plays an important role in the control of normal and pathological behavior. 5-HT2A receptors are widely implicated in the regulation both normal functions and psychopathologies, especially schizophrenia and depression. Here, we investigated implication of 5-HT2A receptor in mechanisms of neurotrophic factors BDNF and GDNF action. We found that the acute intracerebroventricular injection of BDNF produced considerable increase in 5-HT2A receptor functional activity in ASC mice. Moreover, BDNF injection led to the increasing of 5-HT2A receptor gene expression in the hippocampus and its decrease in the frontal cortex without any effects in the midbrain. On the contrary, GDNF injection failed to alter 5-HT2A receptor functional activity, but increased the 5-HT2A receptor gene expression in the frontal cortex without any effects in the hippocampus and midbrain. Thus, an effect of the central administration of the neurotrophic factors BDNF and GDNF on the 5-HT2A receptor functional activity and gene expression was shown. The results indicate the implication of 5-HT2A receptor in the mechanisms of BDNF and GDNF action.

[The role of 5-HT3, 5-HT(1A) receptors and its coaction in the regulation behavior in mice].

Here we investigated whether the 5-HT3 receptor and the 5-HT3/5-HT(1A) receptors coaction play essential role in the regulation of locomotion, depressive-like and social behavior. It was found that central administration of selective agonist of 5-HT3 receptor m-CPBG (2.5, 5.0, 10.0 nmol) produced significant decrease of horizontal and vertical locomotor activity in the open field (OF) test. Selective antagonist of 5-HT(1A) receptor WAY-100635 (2.0 mg/kg (3.7 µmol/kg), i.p.) attenuated the effect of m-CPBG on behavior in the OF test. Selective 5-HT(1A) receptor agonist 8-OH-DPAT (0.25, 0.5, 1.0 mg/kg (0.76, 1.5 and 3.0 µmol/kg correspondingly), i.p.) significantly decreased horizontal and vertical locomotor activity in the OF test as well. The activation of 5-HT3 receptors failed to affect immobility time in the tail suspension test, whereas the activation 5-HT(1A) receptors significantly decreased the immobility time. Administration of m-CPBG also did not produced considerable effect on social behavior. At the same time, 8-OH-DPAT significantly decreased time and number of social contacts. Thus it was shown for the first time that 5-HT3 receptor-induced behavioral response observed in the OF realized mainly via 5-MHT(1A) receptor. Obtained results provide new evidence on the role of 5-HT3 receptors and 5-HT3/5-HT(1A) receptors coaction in the regulation of locomotor activity but not in the depressive-like and social behavior.

Dopamine receptors and key elements of the neurotrophins (BDNF, CDNF) expression patterns during critical periods of ontogenesis in the brain structures of mice with autism-like behavior (BTBR) or its absence (С57BL/6 J).

Analysis of the mechanisms underlying autism spectrum disorder (ASD) is an urgent task due to the ever-increasing prevalence of this condition. The study of critical periods of neuroontogenesis is of interest, since the manifestation of ASD is often associated with prenatal disorders of the brain development. One of the currently promising hypotheses postulates a connection between the pathogenesis of ASD and the dysfunction of neurotransmitters and neurotrophins. In this study, we investigated the expression of key dopamine receptors (Drd1, Drd2), brain-derived neurotrophic factor (Bdnf), its receptors (Ntrkb2, Ngfr) and the transcription factor Creb1 that mediates BDNF action, as well as cerebral dopamine neurotrophic factor (Cdnf) during the critical periods of embryogenesis (e14 and e18) and postnatal development (p14, p28, p60) in the hippocampus and frontal cortex of BTBR mice with autism-like behavior compared to the neurotypical C57BL/6 J strain. In BTBR embryos, on the 14th day of prenatal development, an increase in the expression of the Ngfr gene encoding the p75NTR receptor, which may lead to the activation of apoptosis, was found in the hippocampus and frontal cortex. A decrease in the expression of Cdnf, Bdnf and its receptor Ntrkb2, as well as dopamine receptors (Drd1, Drd2) was detected in BTBR mice in the postnatal period of ontogenesis mainly in the frontal cortex, while in the hippocampus of mature mice (p60), only a decrease in the Drd2 mRNA level was revealed. The obtained results suggest that the decrease in the expression levels of CDNF, BDNF-TrkB and dopamine receptors in the frontal cortex in the postnatal period can lead to significant changes in both the morphology of neurons and dopamine neurotransmission in cortical brain structures. At the same time, the increase in p75NTR receptor gene expression observed on the 14th day of embryogenesis, crucial for hippocampus and frontal cortex development, may have direct relevance to the manifestation of early autism.

Effect of amisulpride on the expression of serotonin receptors, neurotrophic factor BDNF and its receptors in mice with overexpression of the aggregation-prone [R406W] mutant tau protein.

Serotonin 5-HT7 receptors (5-HT7R) are attracting increasing attention as important participants in the mechanisms of Alzheimer's disease and as a possible target for the treatment of various tau pathologies. In this study, we investigated the effects of amisulpride (5-HT7R inverse agonist) in C57BL/6J mice with experimentally induced expression of the gene encoding the aggregation-prone human Tau[R406W] protein in the prefrontal cortex. In these animals we examined short-term memory and the expression of genes involved in the development of tauopathy (Htr7 and Cdk5), as well as biomarkers of neurodegenerative processes - the Bdnf gene and its receptors TrkB (the Ntrk2 gene) and p75NTR (the Ngfr gene). In a short-term memory test, there was no difference in the discrimination index between mice treated with AAV-Tau[R406W] and mice treated with AAV-EGFP. Amisulpride did not affect this parameter. Administration of AAV-Tau[R406W] resulted in increased expression of the Htr7, Htr1a, and Cdk5 genes in the prefrontal cortex compared to AAV-EGFP animals. At the same time, amisulpride at the dose of 10 mg/kg in animals from the AAV-Tau[R406W] group caused a decrease in the Htr7, Htr1a genes mRNA levels compared to animals from the AAV-Tau[R406W] group treated with saline. A decrease in the expression of the Bdnf and Ntrk2 genes in the prefrontal cortex was revealed after administration of AAV-Tau[R406W]. Moreover, amisulpride at various doses (3 and 10 mg/kg) caused the same decrease in the transcription of these genes in mice without tauopathy. It is also interesting that in mice of the AAV-EGFP group, administration of amisulpride at the dose of 10 mg/kg increased the Ngfr gene mRNA level. The data obtained allow us to propose the use of amisulpride in restoring normal tau protein function. However, it should be noted that prolonged administration may result in adverse effects such as an increase in Ngfr expression and a decrease in Bdnf and Ntrk2 expression, which is probably indicative of an increase in neurodegenerative processes.

[Aggression and acoustic startle response in adult and infant rats with genetically defined aggression towards man and its absence].

The aim of the current study was to investigate the association between expression of acoustic startle response and fear-induced aggression. The intensity of aggressive response towards man and acoustic startle response in adult and 15-day old Norway rats selectively bred for 70 generation for high level or the lack of fear-induced aggression was studied. Adult rats of aggressive strain demonstrated high aggression and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. It was found that, in contrast to infant rats of tame strain, 15-day old rat pups of aggressive strain demonstrated distinct aggressive response towards man, although this response was not as intensive as in adult rats of this strain. There was no considerable difference between aggressive and tame infants in amplitude of acoustic startle response. Significant habituation of startle response was shown in adult rats of aggressive strain, whereas in 15-day old rat pups of aggressive rat strain amplitude of startle response remained unaltered. Both adult and infant rats of tame strain demonstrated considerable habituation of startle response. Thus, defensive aggression in rats with genetic predisposition to fear-induced aggression appears quite early--at eyes opening they demonstrate a pronounced aggressive response toward man. The acoustic startle reflex is one of the elements of complex behavior--fear-induced aggression, and this element is involved in the enhancement of aggressive response towards man in adult rats but does not play any essential role in infant aggressiveness.

[Effect of GDNF on the behavior of ASC mice with high hereditary predisposition to catalepsy].

ASC mice, which were selected for high predisposition to catalepsy, are convenient genetic model for research of central mechanisms related to disorder of motor regulation. The aim of the work was to study the effect of glial cell line-derived neurotrophic factor (GDNF) on catalepsy, locomotor activity, stereotyping behavior in the marble burying test and on the dopamine level in striatum of ASC mice. It was shown that GDNF increased the locomotor activity in the open field, reduced catalepsy expression and stimulated the stereotyping obsessive-compulsive behavior. These changes in behavior were accompanied by increasing dopamine level in striatum.

Effects of central administration of the human Tau protein on the Bdnf, Trkb, p75, Mapt, Bax and Bcl-2 genes expression in the mouse brain.

Alzheimer's disease is the most common form of dementia, affecting millions of people worldwide. Despite intensive work by many researchers, the mechanisms underlying Alzheimer's disease development have not yet been elucidated. Recently, more studies have been directed to the investigation of the processes leading to the formation of neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated Tau proteins. Pathological aggregation of this protein leads to the development of neurodegeneration associated with impaired neurogenesis and apoptosis. In the present study, the effects of central administration of aggregating human Tau protein on the expression of the Bdnf, Ntrk2, Ngfr, Mapt, Bax and Bcl-2 genes in the brain of C57Bl/6J mice were explored. It was found that five days after administration of the protein into the fourth lateral ventricle, significant changes occurred in the expression of the genes involved in apoptosis and neurogenesis regulation, e. g., a notable decrease in the mRNA level of the gene encoding the most important neurotrophic factor BDNF (brain-derived neurotrophic factor) was observed in the frontal cortex which could play an important role in neurodegeneration caused by pathological Tau protein aggregation. Central administration of the Tau protein did not affect the expression of the Ntrk2, Ngfr, Mapt, Bax and Bcl-2 genes in the frontal cortex and hippocampus. Concurrently, a significant decrease in the expression of the Mapt gene encoding endogenous mouse Tau protein was found in the cerebellum. However, no changes in the level or phosphorylation of the endogenous Tau protein were observed. Thus, central administration of aggregating human Tau protein decreases the expression of the Bdnf gene in the frontal cortex and the Mapt gene encoding endogenous mouse Tau protein in the cerebellum of C57Bl/6J mice.

[Implication of 5-HT2A receptors in the genetic mechanisms of the brain 5-HT system autoregulation].

Brain serotonin (5-HT) system has been implicated in pathophysiology of anxiety, depression, drug addiction, and schizophrenia. 5-HT2A receptor is involved in the mechanisms of stress-induced psychopathology and impulsive behavior. Here, we investigated the role of 5-HT2A receptor in the autoregulation of the brain 5-HT system. The chronic treatment with agonist of 5-HT2A receptor DOI (1.0 mg/kg, i.p./14 days) produced considerable decrease of 5-HT2A receptor-mediated "head-twitches" in AKR/J mice indicating desensitization of 5-HT2A receptors. Chronic DOI treatment failed to alter 5-HT2A receptor gene expression in the midbrain, hippocampus and frontal cortex. At the same time, the increase in the expression of the gene encoding key enzyme of 5-HT synthesis, tryptophan hydroxylase 2 (TPH2), the increase in TPH2 activity and 5-HT levels and decreased expression of serotonin transporter (5-HTT) gene was found in the midbrain of DOI-treated mice. The results provide new evidence of receptor-gene cross-talk in the brain 5-HT system and the implication of 5-HT2A receptor in the autoregulation of the brain 5-HT system.

[On the role of selective silencer Freud-1 in the regulation of the brain 5-HT(1A) receptor gene expression].

Selective 5-HT(1A) receptor silencer (Freud-1) is known to be one of the main factors for transcriptional regulation of brain serotonin 5-HT(1A) receptor. However, there is a lack of data on implication of Freud-1 in the mechanisms underlying genetically determined and experimentally altered 5-HT(1A) receptor system state in vivo. In the present study we have found a difference in the 5-HT(1A) gene expression in the midbrain of AKR and CBA inbred mouse strains. At the same time no distinction in Freud-1 expression was observed. We have revealed 90.3% of homology between mouse and rat 5-HT(1A) receptor DRE-element, whereas there was no difference in DRE-element sequence between AKR and CBA mice. This indicates the absence of differences in Freud-1 binding site in these mouse strains. In the model of 5-HT(1A) receptor desensitization produced by chronic 5-HT(1A) receptor agonist administration, a significant reduction of 5-HT(1A) receptor gene expression together with considerable increase of Freud-1 expression were found. These data allow us to conclude that the selective silencer of 5-HT(1A) receptor, Freud-1, is involved in the compensatory mechanisms that modulate the functional state of brain serotonin system, although it is not the only factor for 5-HT(1A) receptor transcriptional regulation.

[The role of the glycoprotein gp130 in serotonin mediator system in mouse brain].

Glycoprotein gp130 is involved in signaling out of significant cytokine receptors as interleukin-6 (IL-6), leukemia inhibitory factor and ciliary neurotrophic factor, which play critical role in immunity, inflammation and neurogenesis. IL-6 and brain neurotransmitter serotonin are involved in the mechanism of depression. The aim of this work was to investigat the role of protein gp130 in the regulation of expression of genes, coding the key enzyme of serotonin synthesis--tryptophan hydroxylase 2 (TPH2), 5-HT-transporter, 5-HT(1A)- and 5-HT(2A)-receptors of serotonin. The study was carried out on adult mouse males of AKR and congenic AKR.CBA-D13Mit76 strains, created by transfer of the fragment of chromosome 13 containing the gene coding gp130 protein from CBA/Lac strain to the genome of AKR/J strain. Decreased expression of 5-HT(1A) - 5-HT(2A)-receptor genes in hippocampus midbrain and TPH2 gene in midbrain in AKR.CBA-D13Mit76 mice compared with AKR mice were shown. Activation of nonspecific immunity by bacterial endotoxin lipopolysaccharide (LPS) administration did not affect the genes expression in AKR mice, but increased 5-HT(2A)-receptor expression in midbrain and decreased 5-HT(1A)-receptor expression in cortex in AKR.CBA-D13Mit76 mice. The results indicate: 1) the participation of gp130 in the regulation of TPH2, 5-HT(1A)- and 5-HT(2A)-receptor genes and 2) association of this protein in the genetically determined sensitivity to LPS.

Effect of mouse chromosome 13 terminal fragment on liability to catalepsy and expression of tryptophane hydroxylase-2, serotonin transporter, and 5-HT1A receptor genes in the brain.

Congenic mice obtained by genome fragments transfer from one strain to another are a potent tool for studies of the molecular mechanisms of behavioral mutations. The 59-70 cM fragment of chromosome 13 containing the locus determining predisposition to freezing reaction (catalepsy) and the gene encoding 5-HT(1A) receptor were transferred from cataleptic CBA/Lac mice into the genome of catalepsy-resistant AKR/J mice. The impact of this fragment for the severity of catalepsy and expression of genes encoding tryptophane hydroxylase-2, serotonin transporter, and 5-HT(1A) receptor was studied. Half of mice of the resultant congenic AKR.CBA-D13Mit76 strain exhibited pronounced catalepsy, similarly to donor CBA animals. The expression of 5-HT(1A) receptor gene in the midbrain of AKR animals was significantly higher than in CBA. The level of 5-HT(1A) receptor mRNA in AKR.CBA-D13Mit76 animals was significantly higher than in the donor strain. Mice of parental AKR and CBA strains did not differ from each other and from AKR.CBA-D13Mit76 animals by the levels of tryptophane hydroxylase-2 and serotonin transporter genes mRNA. These data prove the location of catalepsy regulating gene in the distal fragment of chromosome 13. The recipient strain genome enhanced the expression of 5-HT(1A) receptor gene in the brain without modulating the expression of catalepsy gene.

Intracerebral administration of brain-derived neurotrophic factor (BDNF) reduces severity of cataleptic freezing in mice with genetic predisposition to catalepsy.

Single administration of brain-derived neurotrophic factor (BDNF) into the lateral ventricle of ASC mice (Antidepressant Sensitive Catalepsy), a model of depression-like state, significantly decreased predisposition to cataleptic freezing in these animals. These findings indicate that BDNF can appear as a promising antidepressant of new generation and that ASC mice can be used as an adequate model for investigations of the mechanisms of behavior modification by BDNF.