Acetylcholine (ACh) release from the medial septum-diagonal band of Broca (MS-DBB) to the hippocampus profoundly alters cellular excitability, network synchronization, and behavioral state. Deficits in cholinergic function induce memory impairments, such as in Alzheimer's disease, while excessive cholinergic activity resulting from nerve agent or organophosphate pesticide poisoning can induce seizures and lead to neuronal death. ACh has diverse pre- and postsynaptic targets onto both glutamatergic and GABAergic cell populations in the hippocampus. Recent evidence has emerged indicating that the actions of ACh can be highly specific, altering the excitability of distinct GABAergic circuits a cell type-specific manner. Although activation of interneurons and principal cells underlie these oscillations, cholinergic synaptic transmission onto specific target cells remains poorly understood due to technical difficulties in systematically studying defined interneuron populations, the lack of information on the density and spatial localization of cholinergic afferents received by hippocampal target cells, and the inability to activate diffusely distributed populations of MS-DBB neurons in a selective yet coordinated manner. Through bulk fiber stimulation, cholinergic responses can be observed only through a cocktail of synaptic receptor antagonists, yet at the same time, this pharmacological isolation prohibits a complete understanding of how MS-DBB transmission impacts the excitability GABAergic and glutamatergic hippocampal networks. Moreover, the recent discovery of GABA and glutamate transmission machinery co-existing in MS-DBB cholinergic neurons raises the possibility of co-transmission, which would not be observed unless MS-DBB cholinergic fibers can be selectively activated with glutamate and GABAA receptors intact. In this proposal, using a combination of photoactivation of MS-DBB afferents, post-hoc immunocytochemical visualization of photoactivated fibers, electrophysiology, and computational modeling, we will test the central hypothesis that the efficacy of MS-DBB cholinergic and GABAergic transmission depends on the postsynaptic interneuron subtype. For the first time, we will be able to define the relationship between the spatial localization of MS-DBB afferents and the physiological consequence of cell type specific modulation.
In Aim 1, we will determine the efficacy of synaptic transmission between MS-DBB cholinergic neurons and postsynaptic hippocampal interneuron subtypes.
In Aim 2, we will determine the efficacy of synaptic transmission between MS-DBB GABAergic neurons and postsynaptic hippocampal interneuron subtypes. Finally, in Aim 3, we will determine the role of M1 mAChRs present on PV cells in cholinergically-induced network oscillations.
Dysfunction of the medial septum-diagonal band of Broca (MS-DBB) is implicated in a large number of neurodegenerative and psychiatric disease states, such as Alzheimer's disease, Parkinson's disease, schizophrenia, and nerve gas and organic pesticide poisoning. A more complete understanding of the efficacy of synaptic transmission from MS-DBB neurons to hippocampal targets will greatly elucidate the role of the MS-DBB in hippocampal information processing, facilitating the development of new therapeutic approaches for these diseases.
|Gábriel, Robert; Erdélyi, Ferenc; Szabó, Gábor et al. (2016) Ectopic transgene expression in the retina of four transgenic mouse lines. Brain Struct Funct 221:3729-41|
|Mei, Feng; Lehmann-Horn, Klaus; Shen, Yun-An A et al. (2016) Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. Elife 5:|
|Yi, Feng; DeCan, Evan; Stoll, Kurt et al. (2015) Muscarinic excitation of parvalbumin-positive interneurons contributes to the severity of pilocarpine-induced seizures. Epilepsia 56:297-309|
|Lawrence, J Josh; Haario, Heikki; Stone, Emily F (2015) Presynaptic cholinergic neuromodulation alters the temporal dynamics of short-term depression at parvalbumin-positive basket cell synapses from juvenile CA1 mouse hippocampus. J Neurophysiol 113:2408-19|
|Wilhelm, Márta; Lawrence, J Josh; Gábriel, Robert (2015) Enteric plexuses of two choline-acetyltransferase transgenic mouse lines: chemical neuroanatomy of the fluorescent protein-expressing nerve cells. Brain Res Bull 111:76-83|
|Smith, Michael O; Ball, Jackson; Holloway, Benjamin B et al. (2015) Measuring Aggregation of Events about a Mass Using Spatial Point Pattern Methods. Spat Stat 13:76-89|
|Stone, Emily; Haario, Heikki; Lawrence, J Josh (2014) A kinetic model for the frequency dependence of cholinergic modulation at hippocampal GABAergic synapses. Math Biosci 258:162-75|
|Yi, Feng; Ball, Jackson; Stoll, Kurt E et al. (2014) Direct excitation of parvalbumin-positive interneurons by M1 muscarinic acetylcholine receptors: roles in cellular excitability, inhibitory transmission and cognition. J Physiol 592:3463-94|
|Sekuli?, Vladislav; Lawrence, J Josh; Skinner, Frances K (2014) Using multi-compartment ensemble modeling as an investigative tool of spatially distributed biophysical balances: application to hippocampal oriens-lacunosum/moleculare (O-LM) cells. PLoS One 9:e106567|
|Cea-del Rio, Christian A; Lawrence, J Josh; Erdelyi, Ferenc et al. (2011) Cholinergic modulation amplifies the intrinsic oscillatory properties of CA1 hippocampal cholecystokinin-positive interneurons. J Physiol 589:609-27|