Search Results (5)

One of the attractive targets for the relief of stress conditions is TRPV1, which is expressed mostly in primary afferent neurons (nociceptors) and in the central nervous system, mainly in the cortex and hippocampus. We evaluated the action of a potent low-molecular-weight antagonist of TRPV1 (AMG517) and peptide modulator of this channel (APHC3) on long-term potentiation (LTP) and Paired-Pulse Ratio (PPR) in the CA3-CA1 region of the hippocampus of mice. In vivo, we used intranasal administration to provide effective peptide delivery into the brain and analyzed the effects of APHC3 in acute stress tests in comparison with intramuscular administration of APHC3, AMG517, and the reference anxiolytic drug Fabomotizole (Fab). In electrophysiology studies, APHC3 significantly enhanced LTP and PPR, while AMG517 enhanced only PPR. Intranasal administration of APHC3 to mice provided a moderate anxiolytic effect in the single dose (0.01 mg/kg). Intramuscular administration of APHC3 and AMG517 significantly reduced acute stress in mice equal to the reference drug Fab. Thus, TRPV1 modulation in either the peripheral or central nervous system is sufficient to produce an anxiolytic-like effect, likely through distinct underlying mechanisms. Full article

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus. Full article

Over the last two decades the combination of brain slice patch clamp electrophysiology with optogenetic stimulation has proven to be a powerful approach to analyze the architecture of neural circuits and (experience-dependent) synaptic plasticity in such networks. Using this combination of methods, originally termed channelrhodopsin-assisted circuit mapping (CRACM), a multitude of measures of synaptic functioning can be taken. The current review discusses their rationale, current applications in the field, and their associated caveats. Specifically, the review addresses: (1) How to assess the presence of synaptic connections, both in terms of ionotropic versus metabotropic receptor signaling, and in terms of mono- versus polysynaptic connectivity. (2) How to acquire and interpret measures for synaptic strength and function, like AMPAR/NMDAR, AMPAR rectification, paired-pulse ratio (PPR), coefficient of variance and input-specific quantal sizes. We also address how synaptic modulation by G protein-coupled receptors can be studied with pharmacological approaches and advanced technology. (3) Finally, we elaborate on advances on the use of dual color optogenetics in concurrent investigation of multiple synaptic pathways. Overall, with this review we seek to provide practical insights into the methods used to study neural circuits and synapses, by combining optogenetics and patch-clamp electrophysiology. Full article

This study demonstrates how exposure to psychosocial crowding stress (CS) for 3, 7, and 14 days affects glutamate synapse functioning and signal transduction in the frontal cortex (FC) of rats. CS effects on synaptic activity were evaluated in FC slices of the primary motor cortex (M1) by measuring field potential (FP) amplitude, paired-pulse ratio (PPR), and long-term potentiation (LTP). Protein expression of GluA1, GluN2B mGluR1a/5, VGLUT1, and VGLUT2 was assessed in FC by western blot. The body’s response to CS was evaluated by measuring body weight and the plasma level of plasma corticosterone (CORT), adrenocorticotropic hormone (ACTH), and interleukin 1 beta (IL1B). CS 3 14d increased FP and attenuated LTP in M1, while PPR was augmented in CS 14d. The expression of GluA1, GluN2B, and mGluR1a/5 was up-regulated in CS 3d and downregulated in CS 14d. VGLUTs expression tended to increase in CS 7d. The failure to blunt the effects of chronic CS on FP and LTP in M1 suggests the impairment of habituation mechanisms by psychosocial stressors. PPR augmented by chronic CS with increased VGLUTs level in the CS 7d indicates that prolonged CS exposure changed presynaptic signaling within the FC. The CS bidirectional profile of changes in glutamate receptors’ expression seems to be a common mechanism evoked by stress in the FC. Full article

Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons. Full article