Presence Of GABA Antagonists Research Articles

Dysregulation of the hippocampal neuronal network by LGI1 auto-antibodies.

LGI1 is a neuronal secreted protein highly expressed in the hippocampus. Epileptic seizures and LGI1 hypo-functions have been found in both ADLTE, a genetic epileptogenic syndrome and LGI1 limbic encephalitis (LE), an autoimmune disease. Studies, based mainly on transgenic mouse models, investigated the function of LGI1 in the CNS and strangely showed that LGI1 loss of function, led to a decreased AMPA-receptors (AMPA-R) expression. Our project intends at better understanding how an altered function of LGI1 leads to epileptic seizures. To reach our goal, we infused mice with LGI1 IgG purified from the serum of patients diagnozed with LGI1 LE. Super resolution imaging revealed that LGI1 IgG reduced AMPA-R expression at the surface of inhibitory and excitatory neurons only in the dentate gyrus of the hippocampus. Complementary electrophysiological approaches indicated that despite reduced AMPA-R expression, LGI1 IgG increased the global hyperexcitability in the hippocampal neuronal network. Decreased AMPA-R expression at inhibitory neurons and the lack of LGI1 IgG effect in presence of GABA antagonist on excitability, led us to conclude that LGI1 function might be essential for the proper functioning of the overall network and orchestrate the imbalance between inhibition and excitation. Our work suggests that LGI1 IgG reduced the inhibitory network activity more significantly than the excitatory network shedding lights on the essential role of the inhibitory network to trigger epileptic seizures in patients with LGI1 LE.

Frequency filtering of vestibular signals by synaptic transmission in brainstem slices

Frequency-modulated (FM) signals are present in neural systems that are characterized by high discharge rates and continuously-varying stimulus parameters, such as the vestibular system. In the medial vestibular nucleus (MVN) a rate code is used to encode the speed of head rotation and the modulating frequency is equal to the rotation frequency. During rotation in the 1–10 Hz range, many neurons in the medial vestibular nucleus (MVN) have frequency-dependent responses. The role of synaptic processes such as summation and short-term plasticity in the frequency dependence of MVN responses has not been established. Vestibular afferents to the MVN are tonically active in the range of 100 spikes/s, modulated in proportion to head velocity. We asked whether this velocity signal is filtered by synaptic transmission in the brainstem. We found short-term depression and summation of the evoked EPSPs in nearly all MVN cells. Responses to FM pulse trains were dominated by summation of EPSPs, so that membrane potential was approximately sinusoidal during continuous FM stimulation. Responses were highly dependent on the modulating frequency. In the presence of GABA antagonists, postsynaptic potential showed a variety of frequency responses. Long-lasting EPSPs were associated with low-pass filtering of the modulating signal. Short EPSPs were associated with high-pass filtering. Short-term depression resulted in distortion of the sinusoidal response. Modeling using depression and recovery duplicated the form of the responses but failed to simulate the frequency response. We conclude that synaptic transmission between primary afferents and MVN neurons may contribute to frequency filtering in the vestibular pathway.

Control of spontaneous epileptiform discharges by extracellular potassium: an ?in vitro? study in the CA1 subfield of the hippocampal slice

1. The effects evoked by changing [K+]o upon the synchronous epileptiform discharges (SEDs) generated in the presence of GABA antagonists were studied in the "in vitro" hippocampal slice with extra- and intracellular recordings. [K+] in the artificial cerebrospinal fluid (ACSF) was varied in steps of 1 or 2 mM between 3.25 and 10.25 mM. 2. Spontaneous SEDs occurred rarely at [K+]o lower than 5.25 mM. Augmenting [K+]o from 5.25 to 10.25 mM caused a four to five fold increase in the frequency of occurrence of SEDs while the duration of each SED was inversely related to the rate of occurrence. 3. Similar findings were observed when the CA1 subfield had been surgically disconnected from the CA2-CA3 subfields. In these experiments SEDs occurred independently in the two regions, but at any given [K+]o SEDs in the CA3 subfield displayed a frequency two to three times higher than that of SEDs generated in the CA1 area. 4. The intracellular correlate of the SEDs in the CA1 subfield either intact or isolated from the CA2-CA3 ones was a large amplitude depolarization (duration 100-600 ms) associated with a burst of action potentials. This intracellular event, which was similar to the paroxysmal depolarizing shift (PDS) recorded in focal models of epilepsy "in vivo", behaved largely like a synaptic phenomenon when the resting membrane potential (Vm) was changed with intracellularly injected current. A long lasting (half-width: 0.3-2 s in 6.25 mM [K+]o) hyperpolarizing potential usually followed the PDS and could be inverted by hyperpolarizing the Vm by 15-25 mV. When [K+] in the ACSF was raised from 7.25 to 10.25 mM, pyramidal cells depolarized in a dose related fashion. At the same time the post-PDS hyperpolarization decreased in duration and peaked earlier, thus curtailing the depolarizing envelope of the PDS. Consequently, the effect of increasing [K+]o was that of evoking more frequent, but shorter PDSs. 6. These findings demonstrate that the appearance of spontaneous SEDs in the presence of GABA antagonists is dependent upon [K+]o. The effects of evoked by increasing [K+]o are presumably mediated through: (i) a decreased strength of K+ repolarizing conductances; (ii) an increased efficacy of synaptic potentials; (iii) a steady depolarization of the neuronal membrane. The modulation of the frequency of occurrence of SEDs appears to be related to a decreased duration of the hyperpolarization which follows the PDS, a potential which is largely mediated by a K+ conductance.