Glial cell line-derived neurotrophic factor (GDNF) is widely recognized as a survival factor for dopaminergic neurons, but GDNF has also been shown to promote development, differentiation, and ...protection of other central nervous system neurons and was thought to play an important role in various neuropsychiatric disorders. Severe mood disorders, such as primarily major depressive disorder and bipolar affective disorder, attract particular attention. These psychopathologies are characterized by structural alterations accompanied by the dysregulation of neuroprotective and neurotrophic signaling mechanisms required for the maturation, growth, and survival of neurons and glia. The main objective of this review is to summarize the recent findings and evaluate the potential role of GDNF in the pathogenesis and treatment of mood disorders. Specifically, it describes (1) the implication of GDNF in the mechanism of depression and in the effect of antidepressant drugs and mood stabilizers and (2) the interrelation between GDNF and brain neurotransmitters, playing a key role in the pathogenesis of depression. This review provides converging lines of evidence that (1) brain GDNF contributes to the mechanism underlying depressive disorders and the effect of antidepressants and mood stabilizers and (2) there is a cross-talk between GDNF and neurotransmitters representing a feedback system: GDNF-neurotransmitters and neurotransmitters-GDNF.
Heterodimerization between 5‐HT7 and 5‐HT1A receptors seems to play an important role in the mechanism of depression and antidepressant drug action. It was suggested that the shift of the ratio ...between 5‐HT1A/5‐HT7 hetero‐ and 5‐HT1A/5‐HT1A homodimers in presynaptic neurons toward 5‐HT1A/5‐HT1A homodimers is one of the reasons of depression. Consequently, the artificial elevation of 5‐HT7 receptor number in presynaptic terminals might restore physiological homo‐/heterodimer ratio resulting in antidepressive effect. Here we showed that adeno‐associated virus (AAV)‐based 5‐HT7 receptor overexpression in the midbrain raphe nuclei area produced antidepressive effect in male mice of both C57Bl/6J and genetically predisposed to depressive‐like behavior ASC (antidepressant sensitive cataleptics) strains. These changes were accompanied by the elevation of 5‐HT7 receptor mRNA level in the frontal cortex of C57Bl/6J and its reduction in the hippocampus of ASC mice. The presence of engineered 5‐HT7 receptor in the midbrain of both mouse strains was further demonstrated. Importantly that 5‐HT7 receptor overexpression resulted in the reduction of 5‐HT1A receptor level in the membrane protein fraction from the midbrain samples of C57Bl/6J, but not ASC, mice. 5‐HT7 receptor overexpression caused an increase of 5‐HIAA/5‐HT ratio in the midbrain and the frontal cortex of C57Bl/6J and in all investigated brain structures of ASC mice. Thus, 5‐HT7 receptor overexpression in the raphe nuclei area affects brain 5‐HT system and causes antidepressive effect both in C57Bl/6J and in “depressive” ASC male mice. Obtained results indicate the involvement of 5‐HT7 receptor in the mechanisms underlying depressive behavior.
5‐HT7 receptor overexpression in the midbrain produces antidepressive effect in both “normal” C57Bl/6J and “depressive” ASC/Icg mice. This effect is accompanied by increased 5‐HT metabolism.
The mechanisms of autism are of extreme interest due to the high prevalence of this disorder in the human population. In this regard, special attention is given to the transcription factor Freud-1 ...(encoded by the
Cc2d1a
gene), which regulates numerous intracellular signaling pathways and acts as a silencer for 5-HT
1A
serotonin and D2 dopamine receptors. Disruption of the Freud-1 functions leads to the development of various psychopathologies. In this study, we found an increase in the expression of the
Cc2d1a
/Freud-1 gene in the hippocampus of BTBR mice (model of autistic-like behavior) in comparison with C57Bl/6J mice and examined how restoration of the
Cc2d1a
/Freud-1 expression in the hippocampus of BTBR mice affects their behavior, expression of 5-HT
1A
serotonin and D2 dopamine receptors, and CREB and NF-κB intracellular signaling pathways in these animals. Five weeks after administration of the adeno-associated viral vector (AAV) carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a small hairpin RNA (shRNA) that suppressed expression of the
Cc2d1a
/Freud-1 gene, we observed an elevation in the anxiety levels, as well as the increase in the escape latency and path length to the platform in the Morris water maze test, which was probably associated with a strengthening of the active stress avoidance strategy. However, the
Cc2d1a
/Freud-1 knockdown did not affect the spatial memory and phosphorylation of the CREB transcription factor, although such effect was found in C57Bl/6J mice in our previous study. These results suggest the impairments in the CREB-dependent effector pathway in BTBR mice, which may play an important role in the development of the autistic-like phenotype. The knockdown of
Cc2d1a
/Freud-1 in the hippocampus of BTBR mice did not affect expression of the 5-HT
1A
serotonin and D2 dopamine receptors and key NF-κB signaling genes (
Nfkb1
and
Rela
). Our data suggest that the transcription factor Freud-1 plays a significant role in the pathogenesis of anxiety and active stress avoidance in autism.
In this study, OXYS rats of three ages (1, 3, and 6 months), a proven model of Alzheimer's disease (AD), at various stages of disease progression were used to thoroughly study the effects of ...amisulpride on behavior and tau protein phosphorylation.
With the growing number of patients with AD, the problem of finding a cure is very acute. Neurodegeneration in AD has various causes, one of which is hyperphosphorylation of tau protein.
This study aimed to investigate whether amisulpride would affect pathological tau phosphorylation in AD.
We assessed the influence of chronic administration of amisulpride (3 weeks, 3 mg/kg per day, intraperitoneally)-a 5-HT7 receptor inverse agonist-on behavior and tau hyperphosphorylation in OXYS rats (at ages of 1, 3, and 6 months).
Chronic administration of amisulpride dramatically decreased tau phosphorylation in the frontal cortex and hippocampus of 3-month-old OXYS rats. Additionally, in 1- and 3-month-old rats' hippocampi, amisulpride diminished the mRNA level of the Cdk5 gene encoding one of the main tau kinases involved in the 5-HT7 receptor-induced effect on tau phosphorylation.
Thus, We found that chronic administration of amisulpride could reduce pathological tau hyperphosphorylation while reducing anxiety. We propose amisulpride to have therapeutic potential against AD and that it can be the most effective in the early stages of the disease.
The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant ...fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73–110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT1A receptors to chronic 8-OH-DPAT administration and higher 5-HT1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.
The cerebral dopamine neurotrophic factor (CDNF) together with the mesencephalic astrocyte-derived neurotrophic factor (MANF) form a unique family of neurotrophic factors (NTFs) structurally and ...functionally different from other proteins with neurotrophic activity. CDNF has no receptors on the cell membrane, is localized mainly in the cavity of endoplasmic reticulum (ER), and its primary function is to regulate ER stress. In addition, CDNF is able to suppress inflammation and apoptosis. Due to its functions, CDNF has demonstrated outstanding protective and restorative properties in various models of neuropathology associated with ER stress, including Parkinson’s disease (PD). That is why CDNF already passed clinical trials in patients with PD. However, despite the name, CDNF functions extend far beyond the dopamine system in the brain. In particular, there are data on participation of CDNF in the maturation and maintenance of other neurotransmitter systems, regulation of the processes of neuroplasticity and non-motor behavior. In the present review, we discuss the features of CDNF structure and functions, its protective and regenerative properties.
•BDNF system is involved in genetically defined fear-induced aggressive behavior.•Both BDNF mRNA and protein expression are increased in brain structures directly involved in regulation of aggressive ...behavior.•Truncated form of TrkB receptor is predominant in highly aggressive rats.
Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA levels, as well as TrkB and p75NTR receptors mRNA and protein levels, were studied in the brain of rats, selectively bred for more than 85 generations for either the high level or the lack of fear-induced aggressive behavior. Furthermore, we have found that rats of aggressive strain demonstrated both high level of aggression toward humans and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. Significant increase in the BDNF mRNA, mature BDNF and proBDNF protein levels in the raphe nuclei (RN), hippocampus (Hc), nucleus accumbens (NAcc), amygdala, striatum and hypothalamus (Ht) of aggressive rats was revealed. The BDNF/proBDNF ratio was significantly reduced in the Hc and NAcc of highly aggressive rats suggesting prevalence of the proBDNF in these structures. In the Hc and frontal cortex (FC) of aggressive rats, the level of the full-length TrkB (TrkB-FL) receptor form was decreased, whereas the truncated TrkB (TrkB-T) protein level was increased in the RN, FC, substantia nigra and Ht. The TrkB-FL/TrkB-T ratio was significantly decreased in highly aggressive rats suggesting TrkB-T is predominant in highly aggressive rats. The p75NTR expression was slightly changed in majority of studied brain structures of aggressive rats. The data indicate the BDNF system in the brain of aggressive and nonaggressive animals is extremely different at all levels, from transcription to reception, suggesting significant role of BDNF system in the development of highly aggressive phenotype.
Serotonin 5-HT
2A
receptors and the brain-derived neurotrophic factor (BDNF) are involved in the pathophysiology and treatment of many psychiatric diseases. However, the interaction between 5-HT
2A
...and BDNF is still poorly understood. In the present paper, the effects of chronic treatment with mixed 5-HT
2A/2C
receptor agonist DOI, highly selective 5-HT
2A
agonists TCB-2 and 25CN-NBOH on behavior and the BDNF system have been investigated. Chronic treatment of males of C57Bl/6 mice with DOI, TCB-2 and 25CN-NBOH (1 mg/kg, i.p., 14 days) resulted in desensitization of 5-HT
2A
receptors. Treatment with 25CN-NBOH significantly increased startle amplitude. At the same time all used drugs failed to affect anxiety, exploratory and stereotyped behavior as well as spatial memory and learning. TCB-2 and 25CN-NBOH increased the BDNF mRNA level. All 5-HT
2A
agonists increased the proBDNF level but failed to alter the mature BDNF protein level. TrkB and p75
NTR
mRNA levels were affected by all utilized agonists. All drugs decreased the total level as well as membrane TrkB protein one indicating downregulation of TrkB receptors. All agonists decreased the membrane p75
NTR
protein level. Thus, we have shown for the first time that the chronic activation of the 5-HT
2A
receptor with agonists has affected the BDNF system almost on all levels—transcription, proBDNF production, TrkB and p75
NTR
receptors’ level. The obtained data suggested possible suppression in BDNF-TrkB signaling under chronic treatment with 5-HT
2A
agonists.
Cerebral dopamine neurotrophic factor (CDNF) is a promising agent for Parkinson’s disease treatment. However, its role in regulation of non-motor behavior including various psychopathologies remains ...unclear. In this regard, the aim of the present work was to study effect of CDNF overexpression in hippocampus on behavior of the ASC mice (Antidepressant Sensitive Cataleptics) with genetic predisposition to depressive-like behavior. CDNF overexpression in the mouse hippocampal neurons was induced using an adeno-associated viral vector. Four weeks after stereotaxic injection of the AAV-CDNF construct into the dorsal hippocampus home cage activity, exploratory, anxious and depressive-like types of behavior, as well as spatial and associative learning were assessed. We found significant improvements in the dynamics of spatial learning in the Morris water maze in the CDNF-overexpressing animals. At the same time, no effect of CDNF was found on other types of behavior under study. Behavior of the experimental animals under home cage conditions did not differ from that in the control group, except for the decrease in the total amount of food eaten and slight increase in the number of sleep episodes during the light phase of the day. In the present study we also attempted to determine molecular basis for the above-mentioned changes through assessment of the gene expression pattern. We did not find significant changes in the mRNA level of key kinases genes involved in neuroplasticity and neuronal survival, as well as genes encoding receptors for the main neurotransmitter systems. However, the CDNF-overexpressing animals showed increased level of the spliced Xbp indicating activation of the Ire1α/Xbp-1 pathway traditionally associated with ER stress. Immunohistochemical analysis showed that CDNF was co-localized with the ER marker calreticulin. Thus, the effects of endogenous CDNF on behavior that we have found could be mediated by a specific molecular cascade, which emphasizes its difference from the classical neurotrophic factors.
Heterodimerization between 5-HT
and 5-HT
receptors seems to play an important role in the mechanism of depression and antidepressant drug action. It was suggested that the shift of the ratio between ...5-HT
/5-HT
hetero- and 5-HT
/5-HT
homodimers in presynaptic neurons toward 5-HT
/5-HT
homodimers is one of the reasons of depression. Consequently, the artificial elevation of 5-HT
receptor number in presynaptic terminals might restore physiological homo-/heterodimer ratio resulting in antidepressive effect. Here we showed that adeno-associated virus (AAV)-based 5-HT
receptor overexpression in the midbrain raphe nuclei area produced antidepressive effect in male mice of both C57Bl/6J and genetically predisposed to depressive-like behavior ASC (antidepressant sensitive cataleptics) strains. These changes were accompanied by the elevation of 5-HT
receptor mRNA level in the frontal cortex of C57Bl/6J and its reduction in the hippocampus of ASC mice. The presence of engineered 5-HT
receptor in the midbrain of both mouse strains was further demonstrated. Importantly that 5-HT
receptor overexpression resulted in the reduction of 5-HT
receptor level in the membrane protein fraction from the midbrain samples of C57Bl/6J, but not ASC, mice. 5-HT
receptor overexpression caused an increase of 5-HIAA/5-HT ratio in the midbrain and the frontal cortex of C57Bl/6J and in all investigated brain structures of ASC mice. Thus, 5-HT
receptor overexpression in the raphe nuclei area affects brain 5-HT system and causes antidepressive effect both in C57Bl/6J and in "depressive" ASC male mice. Obtained results indicate the involvement of 5-HT
receptor in the mechanisms underlying depressive behavior.
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