Brain function requires precisely orchestrated connectivity between neurons. Establishment of these connections is believed to require signals secreted from outgrowing axons, followed by synapse formation between selected neurons. Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmitter secretion from synaptic vesicles throughout development. However, this does not prevent normal brain assembly, including formation of layered structures, fiber pathways, and morphologically defined synapses. After assembly is completed, neurons undergo apoptosis, leading to widespread neurodegeneration. Thus, synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections.

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.

Acquired neuromyotonia is characterized by hyperexcitability of motor nerves leading to muscle twitching, cramps, and weakness. The symptoms may improve following plasma exchange, and injection of immunoglobulin G (IgG) from 1 neuromyotonia patient into mice increased the resistance of neuromuscular transmission to d-tubocurarine. Here we examine nerves and muscle in vitro from mice injected with plasma or purified IgG from 6 neuromyotonia patients or pooled control subjects, and cultured dorsal root ganglion cells after treatment with IgG. Three of the patients had antibodies against human voltage-gated potassium channels labeled with 125I-alpha-dendrotoxin. The quantal release of acetylcholine (quantal content) at end-plates in diaphragms from mice treated with neuromyotonia IgG preparations was increased by 21% relative to control values (p = 0.0053). With one IgG preparation, the duration of the superficial peroneal nerve compound action currents was increased by 93%. The dorsal root ganglion cells treated with this IgG showed a marked increase in repetitive firing of action potentials. All effects were similar to those obtained with aminopyridines. We conclude that at least some patients with acquired neuromyotonia have antibodies directed against aminopyridine- or alpha-dendrotoxin-sensitive K+ channels in motor and sensory neurons, and they are likely to be implicated in the disease process.

The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema.