Serum response factor (SRF) is a major transcription factor that regulates the expression of several plasticity-associated genes in the brain. Although the developmental expression of SRF in excitatory neurons is crucial for establishing proper hippocampal circuitry, no substantial evidence of its role in unstimulated mature neurons has been provided. The present study used time-controlled, conditional SRF knockout mice and found that the lack of SRF in adult neurons led to decreased actin levels and inactivation of the actin-severing protein cofilin 1 through its increase in phosphorylation at Ser3. The augmentation of cofilin 1 phosphorylation correlated with an alteration of dendritic spine morphology in the dentate gyrus, which was reflected by an increase in the number of spines that clustered into the long-spine category. The changes in spine morphology coincided with a lower amplitude and frequency of miniature excitatory postsynaptic currents. Moreover, SRF knockout animals were hyperactive and exhibited impairments in hippocampus-dependent behaviors, such as digging, marble burying, and nesting. Altogether, our data indicate that the adult deletion of neuronal SRF leads to alterations of spine morphology and function and hippocampus-dependent behaviors. Thus, SRF deletion in adult neurons recapitulates some aspects of morphological, electrophysiological, and behavioral changes that are observed in such psychiatric disorders as schizophrenia and autism spectrum disorders.

Dendritic spines are small dendritic protrusions that harbor most excitatory synapses in the brain. The proper generation and maturation of dendritic spines are crucial for the regulation of synaptic transmission and formation of neuronal circuits.Abnormalities in dendritic spine density and morphology are common pathologies in autism and schizophrenia. According to epidemiological studies, one risk factor for these neurodevelopmental disorders is maternal infection during pregnancy. This review discusses spine alterations in animal models of maternal immune activation in the context of neurodevelopmental disorders. We describe potential mechanisms that might be responsible for prenatal infection-induced changes in the dendritic spine phenotype and behavior in offspring.

W niniejszym artykule przybliżono różne grupy substancji psychoaktywnych, czyli związków chemicznych zmieniających postrzeganie świata. Ich klasyfikacji dokonano na podstawie głównych efektów na psychikę wywoływanych przez te substancje. W artykule wyodrębniono: stymulanty, empatogeny, halucynogeny i depresanty, i scharakteryzowano farmakologiczne mechanizmy działania tych substancji oraz problematykę społeczną w Polsce i w Europie związaną z ich zażywaniem.

Alterations in social behavior are core symptoms of major developmental neuropsychiatric diseases such as autism spectrum disorders or schizophrenia. Hence, understanding their molecular and cellular underpinnings constitutes the major research task. Dysregulation of the global gene expression program in the developing brain leads to modifications in a number of neuronal connections, synaptic strength and shape, causing unbalanced neuronal plasticity, which may be important substrate in the pathogenesis of neurodevelopmental disorders, contributing to their clinical outcome. Serum response factor (SRF) is a major transcription factor in the brain. The behavioral influence of SRF deletion during neuronal differentiation and maturation has never been studied because previous attempts to knock-out the gene caused premature death. Herein, we generated mice that lacked SRF from early postnatal development to precisely investigate the role of SRF starting in the specific time window before maturation of excitatory synapses that are located on dendritic spine occurs. We show that the time-controlled loss of SRF in neurons alters specific aspects of social behaviors in SRF knock-out mice, and causes deficits in developmental spine maturation at both the structural and functional levels, including downregulated expression of the AMPARs subunits GluA1 and GluA2, and increases the percentage of filopodial/immature dendritic spines. In aggregate, our study uncovers the consequences of postnatal SRF elimination for spine maturation and social interactions revealing novel mechanisms underlying developmental neuropsychiatric diseases.

Recently, a well-known anti-alcohol agent, disulfiram (DSF), has gain much interest, as it was found to be effective in the treatment of cocaine abusers, thus also giving hope for patients addicted to opioids and other illicit drugs. Therefore, this study was aimed to investigate the possible outcome that might occur within the subacute co-administration of both morphine (MRF) and DSF in rats, but in the absence of ethanol challenge. As observed, intraperitoneal DSF dose-dependently enhanced MRF-mediated analgesia with the maximal efficacy at a dose of 100 mg/kg. Furthermore, MRF-induced tolerance and aggressive behavior were significantly reduced by DSF (100 mg/kg, i.p.) in comparison to MRF solely. Nonetheless, significant blood biochemical markers of hepatotoxicity were found (i.e., alteration in the levels of glutathione, blood urea nitrogen, etc.), following a combination of both drugs. Likewise, histological analysis of liver tissue revealed severe changes in the group of DSF + MRF, which includes swelling, cell death, damage to certain vessels, and hemorrhages into the liver parenchyma. Our findings indicate that DSF should be used with extreme caution, especially within the course of subacute concomitant use with MRF, as several possible side effects may take place.

Disturbances of gene expression patterns that occur during brain development can severely affect signal transmission, connectivity, and plasticity—key features that underlie memory formation and storage in neurons. Abnormalities at the molecular level can manifest as changes in the structural and functional plasticity of dendritic spines that harbor excitatory synapses. This can lead to such developmental neuropsychiatric conditions as Autism spectrum disorders, intellectual disabilities, and schizophrenia. The present study investigated the role of the major transcriptional regulator serum response factor (SRF) in synapse maturation and its impact on behavioral phenotypes. Using in vitro and in vivo models of early postnatal SRF deletion, we studied its influence on key morphological and physiological hallmarks of spine development. The elimination of SRF in developing neurons resulted in a phenotype of immature dendritic spines and impairments in excitatory transmission. Moreover, using a combination of molecular and imaging techniques, we showed that SRF-depleted neurons exhibited a lower level of specific glutamate receptor mRNAs and a decrease in their surface expression. Additionally, the early postnatal elimination of SRF in hippocampal CA1 excitatory neurons caused spine immaturity and a specific social deficit that is frequently observed in autism patients. Altogether, our data suggest that the regulation of structural and functional dendritic spine maturation begins at the stage of gene transcription, which underpins the crucial role of such transcription factors as SRF. Moreover, disturbances of the postnatal expression of SRF translate to behavioral changes in adult animals.