Spatiotemporal Asymmetry of Associative Synaptic Plasticity in Fear Conditioning Pathways

SummaryInput-specific long-term potentiation (LTP) in afferent inputs to the amygdala serves an essential function in the acquisition of fear memory. Factors underlying input specificity of synaptic modifications implicated in information transfer in fear conditioning pathways remain unclear. Here we show that the strength of naive synapses in two auditory inputs converging on a single neuron in the lateral nucleus of the amygdala (LA) is only modified when a postsynaptic action potential closely follows a synaptic response. The stronger inhibitory drive in thalamic pathway, as compared with cortical input, hampers the induction of LTP at thalamo-amygdala synapses, contributing to the spatial specificity of LTP in convergent inputs. These results indicate that spike timing-dependent synaptic plasticity in afferent projections to the LA is both temporarily and spatially asymmetric, thus providing a mechanism for the conditioned stimulus discrimination during fear behavior

MEF2C Hypofunction in GABAergic Cells Alters Sociability and Prefrontal Cortex Inhibitory Synaptic Transmission in a Sex-Dependent Manner

Background: Heterozygous mutations or deletions of MEF2C cause a neurodevelopmental disorder termed MEF2C haploinsufficiency syndrome (MCHS), characterized by autism spectrum disorder and neurological symptoms. In mice, global Mef2c heterozygosity has produced multiple MCHS-like phenotypes. MEF2C is highly expressed in multiple cell types of the developing brain, including GABAergic (gamma-aminobutyric acidergic) inhibitory neurons, but the influence of MEF2C hypofunction in GABAergic neurons on MCHS-like phenotypes remains unclear. Methods: We employed GABAergic cell type–specific manipulations to study mouse Mef2c heterozygosity in a battery of MCHS-like behaviors. We also performed electroencephalography, single-cell transcriptomics, and patch-clamp electrophysiology and optogenetics to assess the impact of Mef2c haploinsufficiency on gene expression and prefrontal cortex microcircuits. Results: Mef2c heterozygosity in developing GABAergic cells produced female-specific deficits in social preference and altered approach-avoidance behavior. In female, but not male, mice, we observed that Mef2c heterozygosity in developing GABAergic cells produced 1) differentially expressed genes in multiple cell types, including parvalbumin-expressing GABAergic neurons, 2) baseline and social-related frontocortical network activity alterations, and 3) reductions in parvalbumin cell intrinsic excitability and inhibitory synaptic transmission onto deep-layer pyramidal neurons. Conclusions: MEF2C hypofunction in female, but not male, developing GABAergic cells is important for typical sociability and approach-avoidance behaviors and normal parvalbumin inhibitory neuron function in the prefrontal cortex of mice. While there is no apparent sex bias in autism spectrum disorder symptoms of MCHS, our findings suggest that GABAergic cell-specific dysfunction in females with MCHS may contribute disproportionately to sociability symptoms

Tonic Inhibitory Control of Dentate Gyrus Granule Cells by α5-Containing GABAA Receptors Reduces Memory Interference

UNLABELLED Interference between similar or overlapping memories formed at different times poses an important challenge on the hippocampal declarative memory system. Difficulties in managing interference are at the core of disabling cognitive deficits in neuropsychiatric disorders. Computational models have suggested that, in the normal brain, the sparse activation of the dentate gyrus granule cells maintained by tonic inhibitory control enables pattern separation, an orthogonalization process that allows distinct representations of memories despite interference. To test this mechanistic hypothesis, we generated mice with significantly reduced expression of the α5-containing GABAA (α5-GABAARs) receptors selectively in the granule cells of the dentate gyrus (α5DGKO mice). α5DGKO mice had reduced tonic inhibition of the granule cells without any change in fast phasic inhibition and showed increased activation in the dentate gyrus when presented with novel stimuli. α5DGKO mice showed impairments in cognitive tasks characterized by high interference, without any deficiencies in low-interference tasks, suggesting specific impairment of pattern separation. Reduction of fast phasic inhibition in the dentate gyrus through granule cell-selective knock-out of α2-GABAARs or the knock-out of the α5-GABAARs in the downstream CA3 area did not detract from pattern separation abilities, which confirms the anatomical and molecular specificity of the findings. In addition to lending empirical support to computational hypotheses, our findings have implications for the treatment of interference-related cognitive symptoms in neuropsychiatric disorders, particularly considering the availability of pharmacological agents selectively targeting α5-GABAARs. SIGNIFICANCE STATEMENT Interference between similar memories poses a significant limitation on the hippocampal declarative memory system, and impaired interference management is a cognitive symptom in many disorders. Thus, understanding mechanisms of successful interference management or processes that can lead to interference-related memory problems has high theoretical and translational importance. This study provides empirical evidence that tonic inhibition in the dentate gyrus (DG), which maintains sparseness of neuronal activation in the DG, is essential for management of interference. The specificity of findings to tonic, but not faster, more transient types of neuronal inhibition and to the DG, but not the neighboring brain areas, is presented through control experiments. Thus, the findings link interference management to a specific mechanism, proposed previously by computational models

Activation of Tissue Reparative Processes by Glow-Type Plasma Discharges as an Integral Part of the Therapy of Decubital Ulcers

The results of a clinical study of the complex treatment of pressure ulcers using the method of activation of reparative processes in tissues by cold plasma discharges initiated by high-frequency current are presented. Activation was carried out with a specialized device generating cold plasma discharges at frequencies of 0.11, 2.64, and 6.78 MHz. It was shown that the process of activation in the skin and muscle tissues of the bedsore zone proceeds most efficiently when using a current with a frequency of 6.78 MHz as compared to currents with a frequency of 2.64 and 0.11 MHz. For a needle electrode with a diameter of 0.3 mm, the optimal exposure parameters were power—(5.0 ± 1.5) W and time—(2.0–3.0) s. The results of the analysis of histological samples, histochemical, and bacteriological analysis confirmed the effect and showed the dynamics of the process of activation of reparative processes in the tissues of the bedsore wound under the influence of cold plasma discharges and a decrease in microbial contamination. The most pronounced effect of activation was formed during the period from 14 to 21 days. The effectiveness of therapy by the method of activation of reparative processes with cold plasma discharges, according to the criterion of the rate of wound healing, ranged from 14 to 16%, depending on the etiology of the decubitus wound. It is concluded that the activation of tissue reparative processes by glow-type plasma discharges as an integral part of the treatment of decubital ulcers is an effective link in the complex treatment of pressure sores

Activation of Tissue Reparative Processes by Glow-Type Plasma Discharges as an Integral Part of the Therapy of Decubital Ulcers

The results of a clinical study of the complex treatment of pressure ulcers using the method of activation of reparative processes in tissues by cold plasma discharges initiated by high-frequency current are presented. Activation was carried out with a specialized device generating cold plasma discharges at frequencies of 0.11, 2.64, and 6.78 MHz. It was shown that the process of activation in the skin and muscle tissues of the bedsore zone proceeds most efficiently when using a current with a frequency of 6.78 MHz as compared to currents with a frequency of 2.64 and 0.11 MHz. For a needle electrode with a diameter of 0.3 mm, the optimal exposure parameters were power—(5.0 ± 1.5) W and time—(2.0–3.0) s. The results of the analysis of histological samples, histochemical, and bacteriological analysis confirmed the effect and showed the dynamics of the process of activation of reparative processes in the tissues of the bedsore wound under the influence of cold plasma discharges and a decrease in microbial contamination. The most pronounced effect of activation was formed during the period from 14 to 21 days. The effectiveness of therapy by the method of activation of reparative processes with cold plasma discharges, according to the criterion of the rate of wound healing, ranged from 14 to 16%, depending on the etiology of the decubitus wound. It is concluded that the activation of tissue reparative processes by glow-type plasma discharges as an integral part of the treatment of decubital ulcers is an effective link in the complex treatment of pressure sores