Theoretical Investigation of NMDA Effect on the Cerebral Cortex

This thesis examines the dynamical behaviour of incorporating NMDA (an excitatory neurotransmitter) for the electrodynamic model of the cerebral cortex. The model used is the mean-field model developed by Steyn-Ross et al. (2005) which describes the behaviour of the cortex in terms of parameters averaged over spatially localised populations. The behaviour of the model is determined by the four control parameters: inhibitory effect li, subcortical drive s, and NMDA neurotransmitter e ect set by an excitatory factor le and the magnesium concentration C. Adopting this model could give a better understanding of the cortex functionality and the anaesthetic mechanism. The model predicts that there are either one or three stationary states available to the cortex. We identify two of these with highly activated state and a quiescent state and focus on the transition between the two. Theoretical stability predictions (eigenvalue analysis) verified by a numerical simulation show that the system is unstable between the two Hopf bifurcations. In addition, in the stable region the steady states remains stable under a small perturbation, while in the unstable region either a transition between states or a limit cycle (oscillation) occurs depending on the position of the steady state

Deficits in coordinated neuronal activity and network topology are striatal hallmarks in Huntington's disease.

Background. Network alterations underlying neurodegenerative diseases often precede symptoms and functional deficits. Thus, their early identification is central for improved prognosis. In Huntington's disease (HD), the cortico-striatal networks, involved in motor function processing, are the most compromised neural substrate. However, whether the network alterations are intrinsic of the striatum or the cortex is not fully understood. Results In order to identify early HD neural deficits, we characterized neuronal ensemble calcium activity and network topology of HD striatal and cortical cultures. We used large-scale calcium imaging combined with activity-based network inference analysis. We extracted collective activity events and inferred the topology of the neuronal network in cortical and striatal primary cultures from wild-type and R6/1 mouse model of HD. Striatal, but not cortical, HD networks displayed lower activity and a lessened ability to integrate information. GABAA receptor blockade in healthy and HD striatal cultures generated similar coordinated ensemble activity and network topology, highlighting that the excitatory component of striatal system is spared in HD. Conversely, NMDA receptor activation increased individual neuronal activity while coordinated activity became highly variable and undefined. Interestingly, by boosting NMDA activity, we rectified striatal HD network alterations. Conclusions. Overall, our integrative approach highlights striatal defective network integration capacity as a major contributor of basal ganglia dysfunction in HD and suggests that increased excitatory drive may serve as a potential intervention. In addition, our work provides a valuable tool to evaluate in vitro network recovery after treatment intervention in basal ganglia disorders

Pre and Post Synaptic NMDA Effects Targeting Purkinje Cells in the Mouse Cerebellar Cortex

N-methyl-D-aspartate (NMDA) receptors are associated with many forms of synaptic plasticity. Their expression level and subunit composition undergo developmental changes in several brain regions. In the mouse cerebellum, beside a developmental switch between NR2B and NR2A/C subunits in granule cells, functional postsynaptic NMDA receptors are seen in Purkinje cells of neonate and adult but not juvenile rat and mice. A presynaptic effect of NMDA on GABA release by cerebellar interneurons was identified recently. Nevertheless whereas NMDA receptor subunits are detected on parallel fiber terminals, a presynaptic effect of NMDA on spontaneous release of glutamate has not been demonstrated. Using mouse cerebellar cultures and patch-clamp recordings we show that NMDA facilitates glutamate release onto Purkinje cells in young cultures via a presynaptic mechanism, whereas NMDA activates extrasynaptic receptors in Purkinje cells recorded in old cultures. The presynaptic effect of NMDA on glutamate release is also observed in Purkinje cells recorded in acute slices prepared from juvenile but not from adult mice and requires a specific protocol of NMDA application

NMDA Currents Modulate the Synaptic Input–Output Functions of Neurons in the Dorsal Nucleus of the Lateral Lemniscus in Mongolian Gerbils

Neurons in the dorsal nucleus of the lateral lemniscus (DNLL) receive excitatory and inhibitory inputs from the superior olivary complex (SOC) and convey GABAergic inhibition to the contralateral DNLL and the inferior colliculi. Unlike the fast glycinergic inhibition in the SOC, this GABAergic inhibition outlasts auditory stimulation by tens of milliseconds. Two mechanisms have been postulated to explain this persistent inhibition. One, an “integration-based” mechanism, suggests that postsynaptic excitatory integration in DNLL neurons generates prolonged activity, and the other favors the synaptic time course of the DNLL output itself. The feasibility of the integration-based mechanism was tested in vitro in DNLL neurons of Mongolian gerbils by quantifying the cellular excitability and synaptic input–output functions (IO-Fs). All neurons were sustained firing and generated a near monotonic IO-F on current injections. From synaptic stimulations, we estimate that activation of approximately five fibers, each on average liberating ∼18 vesicles, is sufficient to trigger a single postsynaptic action potential. A strong single pulse of afferent fiber stimulation triggered multiple postsynaptic action potentials. The steepness of the synaptic IO-F was dependent on the synaptic NMDA component. The synaptic NMDA receptor current defines the slope of the synaptic IO-F by enhancing the temporal and spatial EPSP summation. Blocking this NMDA-dependent amplification during postsynaptic integration of train stimulations resulted into a ∼20% reduction of the decay time course of the GABAergic inhibition. Thus, our data show that the NMDA-dependent amplification of the postsynaptic activity contributes to the GABAergic persistent inhibition generated by DNLL neurons

The broad differential diagnosis of encephalitis:a case report

A 31-year-old previously healthy woman presented with hallucinations and altered mental status, which was eventually found to be due to anti-N-methyl-D-aspartate receptor encephalitis. In this case report, we discuss the broad differential diagnosis of encephalitis with infectious and autoimmune causes. Furthermore, we consider empirical treatment options in case a definite diagnosis is hard to be made

Effect of Hypobaric Hypoxia Induction on Cognitive Function and Glutamate Receptor in Sprague-Dawley Rats

Induction of sublethal hypoxia provides neuroprotective effect pathological processes such as myocardial infarc and stroke. This study aimed to know the effect of intermittent hypobaric hypoxia (IHH) induction on cognitive function and glutamate receptor in the rat brain. The study was conducted at dr. Saryanto Institute for Aviation and Aerospace Health (LAKESPRA) from 2015-2016. 25 sprague dawley rats, divided into 4 IHH treatment groups and 1 control group. Group 1 was induced with 1x IHH exposure, group 2 was induced with 2x IHH exposure, group 3 was induced with 3x IHH exposure and group 4 was induced with 4x IHH exposure (days 1, 8, 15 and 22). After induction, cognitive function tests are performed with Y Maze and immunohistochemistry is performed to evaluate the glutamate receptor N-methyl-D-aspartic acid (NMDA). There were no significant differences between the four treatment groups compared with the control group (p>0.05) on cognitif function, but significant difference in NMDA receptor. In conclution, HHI induction was not cause change cognitive fuction but increased the response of neuroplasticity of sprague-dawley rats brain tissue which assessed from increasing NMDA receptor.&nbsp

Current and Calcium Responses to Local Activation of Axonal NMDA Receptors in Developing Cerebellar Molecular Layer Interneurons

In developing cerebellar molecular layer interneurons (MLIs), NMDA increases spontaneous GABA release. This effect had been attributed to either direct activation of presynaptic NMDA receptors (preNMDARs) or an indirect pathway involving activation of somato-dendritic NMDARs followed by passive spread of somatic depolarization along the axon and activation of axonal voltage dependent Ca2+ channels (VDCCs). Using Ca2+ imaging and electrophysiology, we searched for preNMDARs by uncaging NMDAR agonists either broadly throughout the whole field or locally at specific axonal locations. Releasing either NMDA or glutamate in the presence of NBQX using short laser pulses elicited current transients that were highly sensitive to the location of the spot and restricted to a small number of varicosities. The signal was abolished in the presence of high Mg2+ or by the addition of APV. Similar paradigms yielded restricted Ca2+ transients in interneurons loaded with a Ca2+ indicator. We found that the synaptic effects of NMDA were not inhibited by blocking VDCCs but were impaired in the presence of the ryanodine receptor antagonist dantrolene. Furthermore, in voltage clamped cells, bath applied NMDA triggers Ca2+ elevations and induces neurotransmitter release in the axonal compartment. Our results suggest the existence of preNMDARs in developing MLIs and propose their involvement in the NMDA-evoked increase in GABA release by triggering a Ca2+-induced Ca2+ release process mediated by presynaptic Ca2+ stores. Such a mechanism is likely to exert a crucial role in various forms of Ca2+-mediated synaptic plasticity