2.3. Morphometric analysis of synapses in the human developing brain in conditions of prenatal exposure to alcohol

Morphometric analysis of synaptic characteristics was performed in the study and control groups, using as a criterion the stage of development of embryos and fetuses.

In the main study group, a significant decrease in all parameters of synaptic structures was revealed in comparison with the control. More detailed analysis of synapse parameters was then performed, taking cognizance of embryo and fetus developmental period (Figures 12–14, Table 2).

We found that the length of postsynaptic density was lower in the main group compared to the control group already at the 7–8th week of gestation. At the 9th week of pregnancy, we identified synaptic contacts, especially at the upper margin of the middle layer. At this period of brain development, all synaptic parameters studied were significantly smaller in the main

group with respect to the control. At week 10, we also noted a decrease in all parameters of the

Figure 13. Morphometric values for presynaptic terminal areas in the control and study groups at different weeks of

Molecular-Cellular Targets of the Pathogenetic Action of Ethanol in the Human Brain in Ontogenesis…

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At 11–12 weeks of development, there was a more pronounced change in the parameters of synaptic contacts in the main group relative to the control group. Most synapses in the brain of the fetuses of 11–12 weeks of gestation are axodendritic positively bent synapses with some insignificant amount of synaptic vesicles and single mitochondria in the presynaptic terminals

The fully formed structure of synaptic connections with the appearance of synaptic vesicles compared to the control, but synapse core area considerably less resulting computermorphometric analysis, we identified a delay of synapses and their structural immaturity which is probably due to a direct effect of alcohol on nerve cells, primarily due to its membranotropic action. Our morphometric studies have revealed that the prenatal influence of alcohol has a pronounced effect on the structural organization of synaptic contacts and their parametric characteristics. Our data confirm the data of other researchers obtained in studies in the culture

study at the synapses; however, the presynaptic perimeters did not differ.

of hippocampal tissues under the influence of a solution of ethanol [50, 51].

of the synapses.

development.

Figure 12. Morphometric values for presynaptic terminal perimeters in the control and study groups at different weeks of development.

with the norm was revealed, which can be critical for neurotransmitter processes in the

2.3. Morphometric analysis of synapses in the human developing brain in conditions of

groups, using as a criterion the stage of development of embryos and fetuses.

Morphometric analysis of synaptic characteristics was performed in the study and control

In the main study group, a significant decrease in all parameters of synaptic structures was revealed in comparison with the control. More detailed analysis of synapse parameters was then performed, taking cognizance of embryo and fetus developmental period (Figures 12–14,

We found that the length of postsynaptic density was lower in the main group compared to the control group already at the 7–8th week of gestation. At the 9th week of pregnancy, we identified synaptic contacts, especially at the upper margin of the middle layer. At this period of brain development, all synaptic parameters studied were significantly smaller in the main

Figure 12. Morphometric values for presynaptic terminal perimeters in the control and study groups at different weeks of

developing human brain.

prenatal exposure to alcohol

Table 2).

84 Drug Addiction

development.

Figure 13. Morphometric values for presynaptic terminal areas in the control and study groups at different weeks of development.

group with respect to the control. At week 10, we also noted a decrease in all parameters of the study at the synapses; however, the presynaptic perimeters did not differ.

At 11–12 weeks of development, there was a more pronounced change in the parameters of synaptic contacts in the main group relative to the control group. Most synapses in the brain of the fetuses of 11–12 weeks of gestation are axodendritic positively bent synapses with some insignificant amount of synaptic vesicles and single mitochondria in the presynaptic terminals of the synapses.

The fully formed structure of synaptic connections with the appearance of synaptic vesicles compared to the control, but synapse core area considerably less resulting computermorphometric analysis, we identified a delay of synapses and their structural immaturity which is probably due to a direct effect of alcohol on nerve cells, primarily due to its membranotropic action. Our morphometric studies have revealed that the prenatal influence of alcohol has a pronounced effect on the structural organization of synaptic contacts and their parametric characteristics. Our data confirm the data of other researchers obtained in studies in the culture of hippocampal tissues under the influence of a solution of ethanol [50, 51].

Thus, as a result of computer-morphometric analysis, we found a delay of synapses and their structural immaturity, which is probably linked to the direct effect of alcohol on nerve cells in

Molecular-Cellular Targets of the Pathogenetic Action of Ethanol in the Human Brain in Ontogenesis…

2.4. Formation of benzodiazepine receptors of the developing human brain of the fetus in

To study the formation of benzodiazepine receptors of the synaptic structures of the brain of the developing fetus in normal and prenatal influences of alcohol, BzDR were investigated by

the brain of fetuses and human embryos. Radioanalysis was performed in a Rack-beta scintillation β-counter. The dissociation constant (Kd) and number of specific binding sites (Bmax) were determined by analysis of saturation curves in Scatchard coordinates. Linear Scatchard blots were analyzed in all cases which confirm the presence of only a specific population of binding sites. Distributions of parameters did not deviate from the normal, so statistical analysis of the data was performed by parametric variational statistics (Student's test) on Statistika 10.0; differences were regarded as significant at p < 0.05. Correlational relationships were assessed by Spearman analysis. Experimental work was carried out in the Department of Clinical Neuroimmunology and Neurobiology of Mental Health Research Institute, Tomsk National Research Medical Center RASci (Tomsk) and in the Laboratory of Clinical Neuromorphology and Laboratory of Clinical Biochemistry of Mental Health Research Center RASci (Moscow). All the studies were approved by the Ethics Committee of the Mental Health

Studies of the properties of human brain BzDR at 8–9 weeks of development showed that

flunitrazepam, in the main study group, related to the increase in the value of Kd (Figure 16, Table 3). The dissociation constant—Kd is inversely proportional to the receptor affinity for their ligand, that is affinity corresponds—1/Kd. The observed increases in Kd indicate a decrease in the affinity of the receptors. The data obtained indicate an increase in the expression of receptors with a decrease in their affinity for the ligand in human embryo brains under

parameters (Kd and Bmax) in compared groups. However, it should be noted that the dynamics of changes in receptor density is discrete, nonlinear. At this period, slight changes in the binding parameters in the control and experimental groups were noted. Density of receptors increases slightly between the 9th and 10th weeks of fetal development. There is some inhibition of growth in receptor density (Figure 16, Table 3), especially in the main group. This correlated with morphometric evaluation of synapses: decreases in presynaptic terminal area and postsynaptic

Alcohol in the early stages of pregnancy, according to the data, negatively affects the formation of synaptic contacts and benzodiazepine receptors in the human brain, reducing the functional

density length in the main experimental group relative to the control group (Table 4).

control group (Figure 15, Table 3). There was a decrease in receptor affinity for the [<sup>3</sup>

At 10 weeks of gestation, there were not expressive changes in [3

H]-flunitrazepam binding site density (Bmax) was greater in the study group than the

H]-flunitrazepam using synaptosomal fraction obtained from

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87

H]-

H]-flunitrazepam-binding

the first place due to its membranotropic action.

conditions of prenatal exposure to alcohol

radio-receptor binding with [<sup>3</sup>

Research Institute.

the prenatal alcohol exposure.

specific [<sup>3</sup>

Figure 14. Morphometric values for postsynaptic density lengths in the control and study groups at different weeks of development.


Notes: C, control group; S, study group (materials from alcoholic mothers). \* Significant differences between study and control groups (p < 0.01).

Table 2. Morphometric parameters of synapses in the human brain at different stages of embryonic development.

Thus, as a result of computer-morphometric analysis, we found a delay of synapses and their structural immaturity, which is probably linked to the direct effect of alcohol on nerve cells in the first place due to its membranotropic action.
