Presynaptic Cell Dependent Modulation of Inhibition in Cortical Regions

Several lines of evidence suggest that the modulation of presynaptic GABA release is mediated by a variety of receptors including; presynaptic AMPA, cannabinoid, GABAB, kainate, metabotropic glutamate, NMDA, and opioid receptors. The evidence supporting presynaptic modulation of inhibition is predominantly obtained from studying stimulus elicited, spontaneous or miniature synaptic events, where the information regarding the identity of the presynaptic cell is lost. This article summarises these findings then focuses on another approach to study the presynaptic modulation of GABA release by comparing the modulation of GABA release at unitary synapses identified morphologically, immunocytochemically and electrophysiologically. To date, evidence for cell-type specific regulation of presynaptic inhibition at identified synapses involving most of the above presynaptic receptors does not exist. Therefore, the key presynaptic modulators that will be focused on here are kainate and cannabinoid receptors and their intracellular signalling cascades that orchestrate GABA release. There will be some discussion on presynaptic modulation via opioid receptors at identified synapses. This review provides evidence to suggest a cell-type specific modulation of presynaptic inhibition in cortical regions

Endocannabinoid Release Modulates Electrical Coupling between CCK Cells Connected via Chemical and Electrical Synapses in CA1

Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholecystokinin (CCK) interneurons which co-express cannabinoid type-1 (CB1) receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of rat hippocampus at P18–20 days. CA1 stratum radiatum CCK Schaffer collateral-associated cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released inhibitory postsynaptic potential (IPSPs) that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5 μM) resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI), maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization

Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease

The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer’s disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aβ) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APPNL-F/NL-F, and APPNL-F/MAPTHTAU and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aβ and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aβ deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11–16 and 18–22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11–14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD

Age-Dependent Sex Differences in Perineuronal Nets in an APP Mouse Model of Alzheimer’s Disease Are Brain Region-Specific

Alzheimer’s disease (AD) is the most common form of dementia, which disproportionately affects women. AD symptoms include progressive memory loss associated with amyloid-β (Aβ) plaques and dismantled synaptic mechanisms. Perineuronal nets (PNNs) are important components of the extracellular matrix with a critical role in synaptic stabilisation and have been shown to be influenced by microglia, which enter an activated state during AD. This study aimed to investigate whether sex differences affected the density of PNNs alongside the labelling of microglia and Aβ plaques density.We performed neurochemistry experiments using acute brain slices from both sexes of the APPNL-F/NL-F mouse model of AD, aged-matched (2–5 and 12–16 months) to wild-type mice, combined with a weighted gene co-expression network analysis (WGCNA). The lateral entorhinal cortex (LEC) and hippocampal CA1, which are vulnerable during early AD pathology, were investigated and compared to the presubiculum (PRS), a region unscathed by AD pathology. The highest density of PNNs was found in the LEC and PRS regions of aged APPNL-F/NL-F mice with a region-specific sex differences. Analysis of the CA1 region using multiplex-fluorescent images from aged APPNL-F/NL-F mice showed regions of dense Aβ plaques near clusters of CD68, indicative of activated microglia and PNNs. This was consistent with the results of WGCNA performed on normalised data on microglial cells isolated from age-matched, late-stage male and female wild-type and APP knock-in mice, which revealed one microglial module that showed differential expression associated with tissue, age, genotype, and sex, which showed enrichment for fc-receptor-mediated phagocytosis. Our data are consistent with the hypothesis that sex-related differences contribute to a disrupted interaction between PNNs and microglia in specific brain regions associated with AD pathogenesis

Alzheimer’s Disease Enhanced Tonic Inhibition is Correlated With Upregulated Astrocyte GABA Transporter-3/4 in a Knock-In APP Mouse Model

Cognitive decline is a major symptom in Alzheimer’s disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in APP knock-in mouse model of AD and whether this is correlated with changes in principal cell excitability. Using the APPNL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. We observed a higher expression of GAD67, an enzyme that catalyses GABA production, and GAT3/4 in reactive astrocytes labelled with GFAP, which correlated with an enhanced tonic inhibition in the CA1 and DG of 12–16 month-old APPNL-F/NL-F mice compared to the age-matched wild-type animals. Comparative neuroanatomy experiments performed using post-mortem brain tissue from human AD patients, age-matched to healthy controls, mirrored the results obtained using mice tissue. Blocking GAT3/4 associated tonic inhibition recorded in CA1 and DG principal cells resulted in an increased membrane input resistance, enhanced firing frequency and synaptic excitation in both wild-type and APPNL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APPNL-F/NL-F mice model. Our data suggest that an alteration in astrocyte GABA homeostasis is correlated with increased tonic inhibition in the hippocampus, which probably plays an important compensatory role in restoring AD-associated synaptic hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for A

Time-coded neurotransmitter release at excitatory and inhibitory synapses.

Communication between neurons at chemical synapses is regulated by hundreds of different proteins that control the release of neurotransmitter that is packaged in vesicles, transported to an active zone, and released when an input spike occurs. Neurotransmitter can also be released asynchronously, that is, after a delay following the spike, or spontaneously in the absence of a stimulus. The mechanisms underlying asynchronous and spontaneous neurotransmitter release remain elusive. Here, we describe a model of the exocytotic cycle of vesicles at excitatory and inhibitory synapses that accounts for all modes of vesicle release as well as short-term synaptic plasticity (STSP). For asynchronous release, the model predicts a delayed inertial protein unbinding associated with the SNARE complex assembly immediately after vesicle priming. Experiments are proposed to test the model's molecular predictions for differential exocytosis. The simplicity of the model will also facilitate large-scale simulations of neural circuits

Health risk assessment of instant noodles commonly consumed in Port Harcourt, Nigeria

The current study investigated the levels of some heavy metals [Lead (Pb), Arsenic (As), Nickel (Ni), Mercury (Hg), Copper (Cu), Cadmium (Cd), Aluminium (Al) and Chromium (Cr)] and Polycyclic Aromatic Hydrocarbons (PAHs) in six brands of instant noodles (CFN, GFC, NGP, GAA, CUN and FCS) commonly consumed in Port Harcourt, Nigeria. Risks of consumption of contaminated noodles were also assessed. Heavy metals content and PAHs were determined using Flame Atomic Absorption Spectrophotometer (AAS) and Gas Chromatography (GC), respectively. Concentration of heavy metals as Pb, Ni, Cu, Al and Cr were detected while As, Hg and Cd were not detected in noodles. High average concentration (mean ± SD mg/kg) of Pb were observed in brands CFN (3.163 ± 0.21) and GFC (1.022 ± 0.08) which were significantly higher (P≤0.05) than in NGP (0.043 ± 0.15) and GAA (0.276 ± 0.18), although all were above WHO permissible limits (0.025 mg/kg). Target Hazard Quotient and Hazard Index for Pb were >1 in brands CFN and GFC indicating unacceptable risk. Results of PAHs showed brands had total PAHs (mg/kg) in the order: CFN >CUN >GAA >NGP >FCS > GFC. Although Carcinogenic Risks associated with these noodles are within permissible range, consumption of CFN and GFC could pose greater health risk to consumers. Long term consumption of brands CUN, CFN and GAA may have higher probability of carcinogenesis among consumers. We therefore recommend more diligent regulatory policies and monitoring by relevant Government agencies (WHO, NAFDAC, CPC and SON) to ensure wholesome noodles get to consumers

CB1 modulation of temporally distinct synaptic facilitation among local circuit interneurons mediated by N-type calcium channels in CA1

One of the critical factors in determining network behavior of neurons is the influence of local circuit connections among interneurons. The short-term synaptic plasticity and the subtype of presynaptic calcium channels used at local circuit connections of inhibitory interneurons in CA1 were investigated using dual whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of P18- to 21-day-old rat stratum radiatum (SR) and stratum lacunosum moleculare (SLM). Two forms of temporally distinct synaptic facilitation were observed among interneuron connections involving presynaptic cholecystokinin (CCK)-positive cells in SR, frequency-dependent facilitation, and a delayed onset of release (45–80 ms) with subsequent facilitation (DORF). Inhibition at both these synapses was under tonic cannabinoid-type 1 (CB1) receptor activity. DORF synapses did not display conventional release-dependent properties; however, blocking CB1 receptors with antagonist AM-251 (10 μM) altered the synaptic transmission to frequency-dependent depression with a fast onset of release (2–4 ms). Presynaptic CCK-negative interneurons in SLM elicited inhibitory postsynaptic potentials (IPSPs) insensitive to CB1 receptor pharmacology displayed frequency-dependent depression. Release of GABA at facilitating synapses was solely mediated via N-type presynaptic calcium channels, whereas depressing synapses utilized P/Q-type channels. These data reveal two distinct models of neurotransmitter release patterns among interneuron circuits that correlate with the subtype of presynaptic calcium channel. These data suggest that endocannabinoids act via CB1 receptors to selectively modulate N-type calcium channels to alter signal transmission