No abstract

Aging is associated with morphological, physiological and metabolic changes, leading to multiorgan degenerative pathologies, such as cognitive function decline. It has been suggested that memory loss also involves a decrease in neurotrophic factors, including brain-derived neurotrophic factor (BDNF). In recent years, microbiota has been proposed as an essential player in brain development, as it is believed to activate BDNF secretion through butyrate production. Thus, microbiota modulation by supplementation with probiotics and prebiotics may impact cognitive decline. This study aimed to evaluate the effects of probiotics and prebiotics supplementation on the memory of middle-aged rats. Sprague-Dawley male rats were randomized in four groups (n = 13 per group): control (water), probiotic (E. faecium), prebiotic (agave inulin), symbiotic (E. faecium + inulin), which were administered for 5 weeks by oral gavage. Spatial and associative memory was analyzed using the Morris Water Maze (MWM) and Pavlovian autoshaping tests, respectively. Hippocampus was obtained to analyze cytokines [interleukin (IL-1β) and tumor necrosis factor (TNF-α)], BDNF and γ-aminobutyric acid (GABA) by enzyme-linked immunosorbent assay (ELISA). Butyrate concentrations were also evaluated in feces. The symbiotic group showed a significantly better performance in MWM (p < 0.01), but not in Pavlovian autoshaping test. It also showed significantly lower concentrations of pro-inflammatory cytokines (p < 0.01) and the reduction in IL-1β correlated with a better performance of the symbiotic group in MWM (p < 0.05). Symbiotic group also showed the highest BDNF and butyrate levels (p < 0.0001). Finally, we compared the electrophysiological responses of control (n = 8) and symbiotic (n = 8) groups. Passive properties of CA1 pyramidal cells (PCs) exhibited changes in response to the symbiotic treatment. Likewise, this group showed an increase in the N-methyl-D-aspartate receptor (NMDA)/AMPA ratio and exhibited robust long-term potentiation (LTP; p < 0.01). Integrated results suggest that symbiotics could improve age-related impaired memory.

In addition to its prominent role as an energetic substrate in the brain, lactate is emerging as a signaling molecule capable of controlling neuronal excitability. The finding that the lactate-activated receptor (hydroxycarboxylic acid receptor 1; HCA1) is widely expressed in the brain opened up the possibility that lactate exerts modulation of neuronal activity via a transmembranal receptor-linked mechanism. Here, we show that lactate causes biphasic modulation of the intrinsic excitability of CA1 pyramidal cells. In the low millimolar range, lactate or the HCA1 agonist 3,5-DHBA reduced the input resistance and membrane time constant. In addition, activation of HCA1 significantly blocked the fast inactivating sodium current and increased the delay from inactivation to a conducting state of the sodium channel. As the observed actions occurred in the presence of 4-CIN, a blocker of the neuronal monocarboxylate transporter, the possibility that lactate acted via neuronal metabolism is unlikely. Consistently, modulation of the intrinsic excitability was abolished when CA1 pyramidal cells were dialyzed with pertussis toxin, indicating the dependency of a G -protein-coupled receptor. The activation of HCA1 appears to serve as a restraining mechanism during enhanced network activity and may function as a negative feedback for the astrocytic production of lactate.

We performed whole-cell recordings from CA3 s. radiatum (R) and s. lacunosum-moleculare (L-M) interneurons in hippocampal slices to examine the temporal aspects of summation of converging perforant path (PP) and mossy fibre (MF) inputs. PP EPSPs were evoked from the s. lacunosum-moleculare in area CA1. MF EPSPs were evoked from the medial extent of the suprapyramidal blade of the dentate gyrus. Summation was strongly supralinear when examining PP EPSP with MF EPSP in a heterosynaptic pair at the 10 ms ISI, and linear to sublinear at longer ISIs. This pattern of nonlinearities suggests that R and L-M interneurons act as coincidence detectors for input from PP and MF. Summation at all ISIs was linear in voltage clamp mode demonstrating that nonlinearities were generated by postsynaptic voltage-dependent conductances. Supralinearity was not detected when the first EPSP in the pair was replaced by a simulated EPSP injected into the soma, suggesting that the conductances underlying the EPSP boosting were located in distal dendrites. Supralinearity was selectively eliminated with either Ni 2+ (30 μM), mibefradil (10 μM) or nimodipine (15 μM), but was unaffected by QX-314. This pharmacological profile indicates that supralinearity is due to recruitment of dendritic T-type Ca 2+ channels by the first subthreshold EPSP in the pair. Results with the hyperpolarization-activated (I h ) channel blocker ZD 7288 (50 μM) revealed that I h restricted the time course of supralinearity for coincidently summed EPSPs, and promoted linear to sublinear summation for asynchronous EPSPs. We conclude that coincidence detection results from the counterbalanced activation of T-type Ca 2+ channels and inactivation of I h .

The morphological and electrophysiological diversity of inhibitory cells in hippocampal area CA3 may underlie specific computational roles and is not yet fully elucidated. In particular, interneurons with somata in strata radiatum (R) and lacunosum-moleculare (L-M) receive converging stimulation from the dentate gyrus and entorhinal cortex as well as within CA3. Although these cells express different forms of synaptic plasticity, their axonal trees and connectivity are still largely unknown. We investigated the branching and spatial patterns, plus the membrane and synaptic properties, of rat CA3b R and L-M interneurons digitally reconstructed after intracellular labeling. We found considerable variability within but no difference between the two layers, and no correlation between morphological and biophysical properties. Nevertheless, two cell types were identified based on the number of dendritic bifurcations, with significantly different anatomical and electrophysiological features. Axons generally branched an order of magnitude more than dendrites. However, interneurons on both sides of the R/L-M boundary revealed surprisingly modular axo-dendritic arborizations with consistently uniform local branch geometry. Both axons and dendrites followed a lamellar organization, and axons displayed a spatial preference towards the fissure. Moreover, only a small fraction of the axonal arbor extended to the outer portion of the invaded volume, and tended to return towards the proximal region. In contrast, dendritic trees demonstrated more limited but isotropic volume occupancy. These results suggest a role of predominantly local feedforward and lateral inhibitory control for both R and L-M interneurons. Such role may be essential to balance the extensive recurrent excitation of area CA3 underlying hippocampal autoassociative memory function.

No abstract

No abstract

The participation of voltage-sensitive Na+ channels (VSSC) on the changes on internal (i) Na+, K+, Ca2+, and on DA, Glu, and GABA release caused by different concentrations of 4-AP was investigated in striatum synaptosomes. TTX, which abolished the increase in Na(i) (as determined with SBFI), induced by 0.1 mM 4-AP only inhibited by 30% the rise in Na(i) induced by 1 mM 4-AP. One millimolar 4-AP markedly decreased the fluorescence of the K+ indicator dye PBFI but 0.1 mM 4-AP did not. Like 1 mM 4-AP, ouabain decreased PBFI fluorescence and increased a considerable fraction of Na(i) in a TTX-insensitive manner. In contrast with the different TTX sensitivity of the rise in Na(i) induced by 0.1 and 1 mM 4-AP, the rise in Ca(i) (as determined with fura-2) induced by the two concentrations of 4-AP was markedly inhibited by TTX, as well as by omega-agatoxin in combination with omega-conotoxin GVIA, indicating that only the TTX-sensitive fraction of the rise in Na(i) induced by 4-AP is linked with the activation of presynaptic Ca2+ channels. It is concluded that the TTX-sensitive fraction of neurotransmitter release evoked by 4-AP is released by exocytosis, and the TTX insensitive fraction involves reversal of the neurotransmitters transporters. This contrasts with the exocytosis evoked by high K+ that is unchanged by TTX and with the neurotransmitter-transporter-mediated release evoked by veratridine, which is highly TTX sensitive and does not require activation of Ca2+ channels.