Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice

Autor: Arn M. J. M. van den Maagdenberg, Daniela Pietrobon, Dania Vecchia, Angelita Tottene
Rok vydání: 2014
Předmět:
DIV
days in vitro
LJP
liquid junction potential
Migraine with Aura
Cell Culture Techniques
Action Potentials
VIP
vasoactive intestinal peptide
Gating
5HT3aR
5-hydroxytryptamine 3a receptor
Synaptic Transmission
AHP
after-hyperpolarization
CGRP
calcitonin gene-related peptide
APhw
action potential half width
Calcium Channels
N-Type
FHM1
familial hemiplegic migraine type 1
siRNA
small interfering ribonucleic acid
Channelopathy
Fast-spiking interneuron
BME
basal Eagle's medium
Gene Knock-In Techniques
PV
parvalbumin
gamma-Aminobutyric Acid
Cerebral Cortex
GAD
glutamic acid decarboxylase
Migraine
calcium channel
inhibitory synaptic transmission
Voltage-dependent calcium channel
Pyramidal Cells
medicine.anatomical_structure
Neurology
KI
knockin
Excitatory postsynaptic potential
Pyramidal cell
Knockin mouse model
Interneuron
Excitatory–inhibitory balance
Presynaptic Terminals
Mice
Transgenic
Neurotransmission
Biology
Inhibitory postsynaptic potential
Article
Cav2.1
lcsh:RC321-571
PBS
phosphate buffered saline
Interneurons
medicine
Animals
Humans
CSD
cortical spreading depression
SNAP25
synaptosomal-associated protein of 25 kDa
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Migraine
Neural Inhibition
Mice
Inbred C57BL
Disease Models
Animal
inhibitory synaptic transmission
Inhibitory Postsynaptic Potentials
GABA
gamma-aminobutyric acid
Mutation
biology.protein
SOM
somatostatin
Excitatory-inhibitory balance
calcium channel
Calcium
BSA
bovine serum albumin
FS
fast-spiking
Calcium Channels
AP
action potential
Neuroscience
Zdroj: Neurobiology of Disease, 69, 225-234
Neurobiology of Disease, Vol 69, Iss, Pp 225-234 (2014)
Neurobiology of Disease
ISSN: 0969-9961
DOI: 10.1016/j.nbd.2014.05.035
Popis: Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca2+] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory–inhibitory balance in FHM1.
Highlights • Multipolar interneuron autaptic transmission is unaltered in FHM1 knockin mice. • This is due to unaltered action potential (AP)-evoked presynaptic Ca influx. • Unaltered AP-evoked Ca influx is not due to short duration of interneuron APs. • CaV2.1 channels of multipolar interneurons are barely affected by the FHM1 mutation. • This may explain unaltered inhibitory neurotransmission in FHM1.
Databáze: OpenAIRE
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