Methods of modulating GABAergic inhibitory synapse formation and function
The present technology relates to methods of modulating the number of GABAergic synapses between at least two neurons. These methods include contacting at least one of the neurons with a PlexinB agonist or a nucleic acid molecule encoding a PlexinB agonist, such as a composition including a Sema4D polypeptide or an extracellular fragment thereof, or a nucleic acid molecule encoding the Sema4D polypeptide or extracellular fragment thereof. The present technology also relates to methods of modulating neuronal activity in the central nervous system or peripheral nervous system of a subject in need thereof by modulating the number of GABAergic synapses between at least two neurons. The present technology further relates to methods of treating a neurological disorder that would benefit from modulating neuronal activity in the central nervous system or peripheral nervous system of a subject in need thereof.
1. A method of treating a seizure disorder in a subject in need thereof, comprising administering to said subject a composition comprising an effective amount of an extracellular Sema4D polypeptide fragment, or a nucleic acid molecule encoding said extracellular Sema4D polypeptide fragment, wherein the extracellular Sema4D polypeptide fragment has at least 80% identity with amino acid residues 27-490 of SEQ ID NO: 6 and wherein said administering is effective to increase the number of GABAergic synapses between at least two hippocampal neurons that include one inhibitory neuron and one excitatory neuron, with one of said at least two neurons expressing plexinB1 receptor, thereby treating said seizure disorder in the subject.
2. The method of claim 1 , wherein the extracellular Sema4D polypeptide fragment comprises amino acid residues 24-711 or 27-490 of the amino acid sequence of SEQ ID NO: 6 or a corresponding amino acid region in an ortholog thereof.
3. The method of claim 1 , wherein the number of GABAergic synapses formed between at least two neurons of the subject increases without increasing the number of glutamatergic synapses between the two neurons.
4. The method of claim 1 , wherein the inhibitory neuron is an interneuron.
5. The method of claim 1 , further comprising contacting at least one of the neurons with a PlexinB1 polypeptide or a nucleic acid molecule encoding said PlexinB1 polypeptide.
6. The method of claim 1 , wherein the composition is administered directly into the central nervous system of the subject.
7. The method of claim 1 , wherein the seizure disorder is epilepsy.
8. The method of claim 1 , wherein the subject is a human.
9. The method of claim 8 , wherein the subject is an infant or child.
10. The method of claim 1 , wherein said administering is repeated daily.
11. The method of claim 1 , wherein the composition comprises 100 nM of the extracellular Sema4D polypeptide fragment.
12. The method of claim 1 , wherein said administering is carried out using a dosage of at least 50 mg/day.