The objective of this study is to determine the actions and mechanisms of the peptide somatostatin (SST) in normal and epileptic neurotransmission. SST has long been speculated to play a role in epilepsy, however its function is unknown. Our planned studies are based on the following: 1) We have shown that SST strongly reduces epileptiform activity in both CA1 and CA3 regions of hippocampus. SST acts on both evoked and spontaneous epileptiform events, suggesting that this peptide may act to limit the spread of seizures through the hippocampus and to other limbic structures. 2) SST appears to specifically reduce recurrent excitatory feedforward neurotransmission which is critical to the generation of epileptiform events. Recurrent excitatory synapses are increased in epileptic tissue. 3) One of the most consistent findings in eplieptic hippocampus is the selective loss of SST-containing neurons in the hilus of the dentate gyrus. The functional consequence of this loss is unknown, nor has the action of SST in the dentate been characterized. 4) Transgenic mice have been developed with null mutations ( knockouts ) for the SST peptide gene or for selective SST receptor subtype genes. These mice provide a unique tool for studying the function of endogenous SST in the brain. Our preliminary data suggests SST has inhibitory actions in the dentate. Therefore the specific aims of this proposal are: 1) Examine the effects of SST on neurotransmission in the dentate, which acts as a gate through which seizure events enter the hippocampus. 2) Examine the effects of SST in hippocampus which has undergone the synaptic remodeling characteristic of epileptic tissue. 3) Begin studies to examine hyperexcitabilty and SST effects in SST or SST receptor knockout mice. We will perform these studies using intracellular, extracellular, and whole-cell patch clamp techniques. These studies will help determine the function of SST in normal and epileptic brain, and could have therapeutic implications in the treatment of epilepsy and other neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS038633-01A1
Application #
6041589
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Jacobs, Margaret
Project Start
1999-09-30
Project End
2003-07-31
Budget Start
1999-09-30
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Einstein, Emily B; Patterson, Carlyn A; Hon, Beverly J et al. (2010) Somatostatin signaling in neuronal cilia is critical for object recognition memory. J Neurosci 30:4306-14
Nie, Zhiguo; Zorrilla, Eric P; Madamba, Samuel G et al. (2009) Presynaptic CRF1 receptors mediate the ethanol enhancement of GABAergic transmission in the mouse central amygdala. ScientificWorldJournal 9:68-85
Tallent, Melanie K; Qiu, Cuie (2008) Somatostatin: an endogenous antiepileptic. Mol Cell Endocrinol 286:96-103
Qiu, Cuie; Zeyda, Thomas; Johnson, Brian et al. (2008) Somatostatin receptor subtype 4 couples to the M-current to regulate seizures. J Neurosci 28:3567-76
Qiu, Cuie; Johnson, Brian N; Tallent, Melanie K (2007) K+ M-current regulates the transition to seizures in immature and adult hippocampus. Epilepsia 48:2047-58
Tallent, Melanie K; Fabre, Veronique; Qiu, Cuie et al. (2005) Cortistatin overexpression in transgenic mice produces deficits in synaptic plasticity and learning. Mol Cell Neurosci 30:465-75
Baraban, Scott C; Tallent, Melanie K (2004) Interneuron Diversity series: Interneuronal neuropeptides--endogenous regulators of neuronal excitability. Trends Neurosci 27:135-42
Roberto, Marisa; Madamba, Samuel G; Moore, Scott D et al. (2003) Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proc Natl Acad Sci U S A 100:2053-8
Baratta, Michael V; Lamp, Tyra; Tallent, Melanie K (2002) Somatostatin depresses long-term potentiation and Ca2+ signaling in mouse dentate gyrus. J Neurophysiol 88:3078-86
Tallent, M K; Madamba, S G; Siggins, G R (2001) Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms. J Neurosci 21:6940-8