Disturbances in neuroplasticity undoubtedly play an important role in the development of autism spectrum disorders (ASDs). Brain neurotransmitters and brain-derived neurotrophic factor (BDNF) are known as crucial players in cerebral and behavioral plasticity. Such an important neurotransmitter as dopamine (DA) is involved in the behavioral inflexibility of ASD. Additionally, much evidence from human and animal studies implicates BDNF in ASD pathogenesis. Nonetheless, crosstalk between BDNF and the DA system has not been studied in the context of an autistic-like phenotype. For this reason, the aim of our study was to compare the effects of either the acute intracerebroventricular administration of a recombinant BDNF protein or hippocampal adeno-associated-virus–mediated BDNF overexpression on autistic-like behavior and expression of key DA-related and BDNF-related genes in BTBR mice (a widely recognized model of autism). The BDNF administration failed to affect autistic-like behavior but downregulated Comt mRNA in the frontal cortex and hippocampus; however, COMT protein downregulation in the hippocampus and upregulation in the striatum were insignificant. BDNF administration also reduced the receptor TrkB level in the frontal cortex and midbrain and the BDNF/proBDNF ratio in the striatum. In contrast, hippocampal BDNF overexpression significantly diminished stereotypical behavior and anxiety; these alterations were accompanied only by higher hippocampal DA receptor D1 mRNA levels. The results indicate an important role of BDNF in mechanisms underlying anxiety and repetitive behavior in ASDs and implicates BDNF–DA crosstalk in the autistic-like phenotype of BTBR mice.

The serotonin 5-HT_1A receptor is one of the most abundant and widely distributed brain serotonin (5-HT) receptors that play a major role in the modulation of emotions and behavior. The 5-HT_1A receptor gene (Htr1a) is under the control of transcription factor Freud-1 (also known as Cc2d1a/Freud-1). Here, using adeno-associated virus (AAV) constructs in vivo, we investigated effects of a Cc2d1a/Freud-1 knockdown in the hippocampus of C57BL/6J mice on behavior, the brain 5-HT system, and brain-derived neurotrophic factor (BDNF). AAV particles carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a short-hairpin RNA targeting mouse Cc2d1a/Freud-1 mRNA had an antidepressant effect in the forced swim test 5 weeks after virus injection. The knockdown impaired spatiotemporal memory as assessed in the Morris water maze. pAAV_H1-2_shRNA-Freud-1_Syn_EGFP decreased Cc2d1a/Freud-1 mRNA and protein levels. Furthermore, the Cc2d1a/Freud-1 knockdown upregulated 5-HT and its metabolite 5-hydroxyindoleacetic acid but not their ratio. The Cc2d1a/Freud-1 knockdown failed to increase mRNA and protein levels of Htr1a but diminished a 5-HT_1A receptor functional response. Meanwhile, the Cc2d1a/Freud-1 knockdown reduced Creb mRNA expression and CREB phosphorylation and upregulated cFos mRNA. The knockdown enhanced the expression of a BDNF precursor (proBDNF protein), which is known to play a crucial part in neuroplasticity. Our data indicate that transcription factor Cc2d1a/Freud-1 is implicated in the pathogenesis of depressive disorders not only via the 5-HT_1A receptor and transcription factor CREB but also through an influence on BDNF.

Depression is a mental disorder that significantly reduces quality of life, and the discovery of new drug targets is an urgent problem for modern neuroscience. Brain-derived neurotrophic factor (BDNF) and its receptors have been found to participate in mechanisms of depression and antidepressant drugs’ action. In this study, we focused on a less-studied truncated isoform of receptor TrkB: TrkB.T1. Initially, we noticed that the level of TrkB.T1 is low in the hippocampus of Antidepressant-Sensitive Cataleptics (ASC) mice, which are characterized by genetically determined depressive-like behavior in contrast to “normal” C57BL/6J mice. Next, overexpression of TrkB.T1 receptor in hippocampal neurons of ACS mice was induced to clarify the role of this receptor in mechanisms of depressive-like behavior. TrkB.T1 overexpression lowered BDNF protein concentration in the hippocampus. On the behavioral level, TrkB.T1 overexpression severely decreased aggression and enhanced social behavior. Additionally, this excess of receptor TrkB.T1 slightly promoted anxiety and depressive-like behavioral traits without affecting learning and memory. Our results show that this TrkB isoform participates in the control of aggression, anxiety, and depressive-like behavior and in the regulation of BDNF system functioning in ASC mice (genetically predisposed to depressive-like behavior). Considering our findings, we believe that hippocampal receptor TrkB.T1 can be a drug target for the correction of behavioral pathologies.

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse effects of the CDNF injection on feed and water consumption or locomotor activity were observed for 3 days afterwards. Decreases in body weight and sleep duration were transient. CDNF-treated animals demonstrated improved performance on the operant learning task and a substantial decrease in anxiety and behavioral despair. CDNF in all the doses enhanced serotonin (5-HT) turnover in the murine frontal cortex, hippocampus, and midbrain. This alteration was accompanied by changes in the mRNA levels of the 5-HT1A and 5-HT7 receptors and in monoamine oxidase A mRNA and protein levels. We found that CDNF dramatically increased c-Fos mRNA levels in all investigated brain areas but elevated the phosphorylated-c-Fos level only in the midbrain. Similarly, enhanced CREB phosphorylation was found in the midbrain in experimental animals. Additionally, the upregulation of a spliced transcript of XBP1 (UPR regulator) was detected in the midbrain and frontal cortex. Thus, we can hypothesize that exogenous CDNF modulates the UPR pathway and overall neuronal activation and enhances 5-HT turnover, thereby affecting learning and emotion-related behavior.

Chronic ethanol exposure and genetic factors interact to drive neuroadaptations in alcohol use disorders (AUD). However, the system-level coordination of molecular responses across brain regions remains unclear. The 5-HT system and BDNF are key regulators of neuroplasticity in alcoholism. The 5-HT₇ receptor modulates both behavior and serotonin signaling. We investigated midbrain 5-HT₇ overexpression in C57BL/6 mice given 5-week ethanol access. Our results showed complex, region-specific changes in 5-HT and BDNF signaling, as well as selective behavioral alterations. Ethanol abolished the antidepressant-like effect of 5-HT₇ overexpression and increased anxiety-like behavior, without affecting baseline locomotion or novel object recognition. At the molecular level, ethanol suppressed 5-HT₇-mediated CREB/BDNF signaling and differentially regulated 5-HT_1A and 5-HT_2A expression across regions. To extract general principles, we used integrative systems analysis based on population-averaged generalized estimating equations (GEE), and mapped effects in the (t₁, t₂) plane. We identified two regularities: first, regional specificity of responses, and second, divergence across regulatory levels, with opposing effects more frequent at the mRNA level and concordant effects more common at the protein level. These findings suggest that neuroadaptation to combined 5-HT₇ and ethanol factors follows region- and level-specific rules, rather than a single global program, underscoring the value of integrative analysis.