Coloboma contiguous gene deletion encompassing Snap alters hippocampal plasticity.
Mice heterozygous for the semidominant mutation coloboma (Cm/+) display several distinct pathologies including head bobbing, ophthalmic deformation, and locomotor hyperactivity. The Cm/+ mutation comprises a contiguous gene defect which encompasses deletion of the gene Snap encoding the presynaptic nerve terminal protein SNAP-25 that is an integral component of the synaptic vesicle docking and fusion complex. Indeed, SNAP-25 is required for axonal growth and for the regulated release of neurotransmitters at the synaptic cleft. As an extension of our studies on the behavioral deficits exhibited by these mutants, including evaluation of the hyperkinesis and dopamine-related behavioral pharmacology that might be related to attention-deficit hyperactivity disorder in humans, we have studied spontaneous electroencephalographic and evoked potential recordings in the dentate gyrus of halothane-anesthetized Cm/+ and normal (+/+) littermates to evaluate potential physiological abnormalities of synaptic function in these mice. While sensory activation elicited by brief (10 sec) tail-pinch produced 1-2 min of theta rhythmic activity in +/+ mice, theta induction was markedly reduced in Cm/+ mice. There were no significant differences in dentate afferent-evoked population excitatory postsynaptic potential (pEPSP) slopes, pEPSP facilitation, or population spike (PS) amplitudes; however, paired-pulse inhibition of dentate PS amplitudes was significantly increased in Cm/+ mice. Furthermore, although brief high-frequency stimulation of the perforant path produced robust long-term potentiation (LTP) of synaptic responses in the dentate gyrus of +/+ mice, LTP was attenuated in Cm /+ mice. It has been previously demonstrated that dopamine (DA) neurotransmission is essential for induction of one type of hippocampal theta rhythm and also may modulate hippocampal LTP, suggesting that alterations in DA synaptic transmission may underlie the behavioral abnormalities, in particular the hyperactivity, associated with Cm/+ mutant mice.
Steffensen
S C
SC
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Wilson
M C
MC
Henriksen
S J
SJ
D000818:Animals; D018891:Dentate Gyrus / Q000502:physiology; D004558:Electric Stimulation; D004569:Electroencephalography; D005071:Evoked Potentials / Q000502:physiology; D005110:Extracellular Space / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics* / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology; D010812:Physical Stimulation; D051381:Rats; D013569:Synapses / Q000502:physiology; D050825:Synaptosomal-Associated Protein 25; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C494209:Snap25 protein, mouse; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D005680:gamma-Aminobutyric Acid