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High frequency repetitive stimulation of an excitatory input in the hippocampus results in a post-tetanic potentiation (PTP) of short duration (about 3 min) that can be followed by a long-term synaptic potentiation (LTP) of the same excitatory input (Schwartzkroin and Wester, 1975; Andersen et al., 1977). It has been reported that this tetanus-induced LTP cannot be elicited in a Ca²⁺-free medium and is therefore a Ca²⁺-dependent process (Dunwiddie et al., 1978; Dunwiddie and Lynch, 1979; Wigstrӧm et al., 1979). Whether the induction of LTP is directly dependent upon Ca²⁺, or whether, Ca²⁺ is required because synaptic transmission is needed to initiate certain postsynaptic process(es) (a postsynaptic depolarization, for instance) leading to LTP, is unknown. Recent studies from this laboratory showed that both short-term potentiation (STP; with a duration resembling PTP) and LTP can be associatively induced if activation of a test input co-occured with either a tetanic stimulation of separate excitatory inputs or a sufficient depolarization of the postsynaptic neurone (Sastry et al., 1985). In this study, experiments were performed to investigate (1) whether associative STP could be induced when activation of the test input preceded or followed the onset of the conditioning train and (2) whether LTP could be induced in the absence of Ca²⁺ in the extracellular medium if sufficient depolarizations of the presynaptic terminals and postsynaptic neurones were provided. All experiments were performed using the transversely sectioned hippocampal slice preparation. Test stimuli were delivered via an electrode located in the stratum radiatum while the conditioning tetani (100 Hz, 10 pulses per train) were delivered via another electrode located in the recorded from the apical dendritic area of CA₁ neurones. After the initial control stimulation period, 5 conditioning tetani were given at a frequency of 0.2 Hz. The test stimuli either preceded (-) or followed ( + ) the onset of each conditioning train by 0 to 100 ms. When the test stimulus followed the onset of each conditioning train, there was significant STP of the test EPSP up to a conditioning-test interval of +80 ms. When the test stimulus preceded the onset of each conditioning train, there was significant STP of the test EPSP up to a conditioning-test interval of -50 ms. Conditioning tetani that were given without co-activation of the test input resulted in a subsequent depression of the test EPSP. It is suggested that either the test or the conditioning input can initiate some postsynaptic process(es) which can in turn affect the activated presynaptic terminals to increase transmitter release or alter the subsynaptic dendritic properties. For studying the possibility of the induction of LTP in the absence of Ca²⁺ in the extracellular medium, population EPSPs were recorded from apical dendritic area of CA₁ neurones in response to stratum radiatum stimulation. After the control stimulation period, slices were exposed either to Ca²⁺-containing or Ca²⁺-free (with Mn²⁺ and Mg²⁺ replacing Ca²⁺) medium, with the concentration of KC1 at 10 to 80 mM. Long-term potentiation of the population EPSPs was observed following the exposure to high K⁺ in Ca²⁺-free media. Following a brief period of potentiation initially, population EPSPs often exhibited a tendency toward depression after exposure to high K⁺ in Ca²⁺-containing media. LTP induced by high K⁺ in Ca²⁺-free medium could also be observed when a fixed number of axons were being activated, indicating that a recruitment of presynaptic fibres cannot entirely account for the potentiation. LTP of the depolarizing commands were paired with activation of the stratum radiatum while the slices were exposed to Ca²⁺ -free medium (normal concentration of KC1). These results suggest that extracellular Ca²⁺, synaptic transmission and thus subsynaptic receptor activation are not necessary for the induction of LTP as long as sufficient depolarizations of the presynaptic terminals and postsynaptic neurones are provided. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

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Hippocampal GABAergic interneuron deficits are implicated in the pathophysiology of schizophrenia. Postmortem histological analyses show alteration in number and/or function of parvalbumin-expressing (PV+) GABAergic interneurons in the cerebral cortex of these patients. A parallel line of research using functional imaging of cerebral blood flow or volume has shown that hyperactivity of the hippocampus may contribute to psychotic symptoms as well as cognitive deficits in schizophrenia. It is not known if changes in GABA transmission, particularly in the number and function of PV+ interneurons, are causally related to hippocampal hyperactivity and expression of behavioral and cognitive abnormalities in schizophrenia. To help answer this question, we used genetic mouse models with deficits in cortical GABAergic interneuron development to test the hypothesis that a selective deficit in PV+ interneurons in the hippocampus can lead to schizophrenia relevant phenotypes such as hippocampal hyperactivity, dysregulation of the mesolimbic dopamine system, enhanced psychomotor responsiveness to amphetamine, and disruption of hippocampal dependent cognition. Here I describe my studies primarily on a mouse model with a deletion of the cell-cycle gene cyclin D2 (cD2 null). This mutation disrupts interneuron development in the medial ganglionic eminence (MGE), leading to a partial and selective deficit in PV+ interneurons in the neocortex and the hippocampus. I show that the cD2 null mouse shows regionally heterogeneous, persistent structural and functional deficit in PV+ interneurons, with a relatively larger and more functional deficit in the hippocampus. The GABAergic deficit in the hippocampus is associated with signs of disinhibition, such as increased cerebral blood volume as found by functional magnetic resonance imaging (fMRI).Upon establishing the evidence for hippocampal disinhibition in the cyclin D2 null mouse, I examined the relationship between this disinhibition and two areas of neural function know to be altered in psychosis and schizophrenia: Mesostriatal DA system function and hippocampus-mediated cognition. I found that the cD2 null mice showed increased dopamine population activity in the ventral tegmental area and enhanced psychomotor response to amphetamine. The latter was eliminated by a partial lesion of the ventral hippocampus, indicating hippocampal disinhibition as the driver of DA neuron dysregulation. In addition, cD2 null mice showed deficits in cognitive functions that recruit and depend on the hippocampus, such as the contextual and cued fear conditioning. Lastly, to test for a causal relationship between the PV+ interneuron deficit in the hippocampus, and the abnormalities in hippocampal metabolism, imaging phenotype, the mesolimbic dopamine dysfunction and contextual learning and memory, I examined the effects of replacing GABAergic interneurons to the hippocampus. I used transplantation of GABAergic interneuron precursors derived from the medial ganglionic eminence (MGE) into the adult hippocampus of cyclin D2 null mutants. MGE-derived progenitor cells developed into structurally and functionally mature PV+ and other GABAergic cells, and normalized hippocampal hypermetabolism. In addition, the MGE transplants normalized VTA dopamine cell activity, normalized amphetamine sensitivity and improved hippocampus-dependent learning and memory. Taken together, these studies establish the plausibility of a causal relationship between hippocampal PV+ interneuron pathology and psychosis-relevant pathophysiological and cognitive phenotypes. Moreover, they provide a rationale for limbic cortical GABAergic-interneuron-targeted treatment strategies in psychotic disorders.

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Vita. Includes bibliographical references.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2001. / Pages 250-291 are duplicates of pages 328-369. Pages 292-327 are non existant. Table of contents (page v) does not refer to pages 250-291 but does refer to pages 328-369. Bibliography: leaves 117-128.

Thesis (M.S.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains vi, 78 p. : ill. Includes abstract. Includes bibliographical references (p. 55-64).

Thesis (Ph. D.) -- California Institute of Technology, 2010. / Title from home page (viewed 03/03/2010). Advisor and committee chair names found in the thesis' metadata record in the digital repository. Includes bibliographical references.

Synaptic dysfunction is a critical neuropathological feature prior to the formation of extracellular senile plaques and intracellular fibrillary tangles (NFTs) in Alzheimer’s disease (AD). The synapse loss and neurites impairment lead to synaptic dysfunction that can be induced by oligomeric Aβ. The administration of oligomeric Aβ reduced the pre-synaptic vesicle proteins and altered the cytoskeletal proteins. The synaptic vesicles (SVs) playing a crucial role to transport and recycle the SV proteins and neurotransmitters (NTs) in synaptic terminals. However, the uptake and release capabilities of SVs were also disrupted by oligomeric Aβ. The disruption of SVs recycling and neurites impairment attenuate neurotransmission that exacerbates the pathogenesis of AD. Therefore, any agents can maintain the SVs recycling and protect the neurites development that could be a therapeutic target for AD. Testosterone is a male sex steroid hormone, which is a potent therapeutic drug for neurodegenerative diseases. It has been found the neuroprotective effects for neuronal death, but the implication on synaptoprotection is still not clear. This study investigated the neuroprotective effects of testosterone from oligomeric Aβ-induced synaptic dysfunction in primary cultured hippocampal neurons. My study demonstrated that testosterone prevented Aβ-induced reduction of pre-synaptic proteins and shortening neurites. Also, testosterone could protect SVs recycling by increasing SVs unloading capability via estrogenic independent pathway. The findings reinforce the neuroprotective effects of testosterone. They are probably facilitating future development for using the concept of male sex hormone as therapy and the intervention of therapeutic drugs for AD patients. / published_or_final_version / Anatomy / Master / Master of Medical Sciences