| Description |
Memory deficits are a devastating consequence of many neurological disorders including Alzheimer’s disease (AD) and epilepsy. Currently approved treatments for memory impairment in AD are few in number, mechanistically homogenous, and only marginally effective, and there are no approved treatments for memory deficits in epilepsy. Thus, new treatments are needed. One path to new therapy development is to first obtain a mechanistic understanding of existing treatments, including those in development, in order to “fine-tune†their targeted effects or discover new therapeutic approaches. Another strategy is to investigate the underlying pathology causing memory dysfunction in order to identify new therapeutic targets. Research in this dissertation utilized both strategies. Chapter 2 used in vitro electrophysiology and immunohistochemistry to investigate the neurophysiology of 5-HT6 receptors, a target with widely reported nootropic effects. Results from these studies suggest that 5-HT6 receptors bidirectionally modulate inhibitory synaptic transmission in the dentate gyrus (DG) via their direct effects on excitatory mossy cells thought to drive inhibition in the DG. Chapter 3 tested the procognitive and anticonvulsant effects of 5-HT6 receptor antagonists in J20 mice, a transgenic model with pathological hyperexcitability thought to contribute to disease progression. Systemic treatment with a 5-HT6 receptor antagonist improved spatial pattern processing in nontransgenic (NTG) mice, but not in J20 mice. Additionally, J20 mice had significantly a lower seizure threshold during the minimal clonic seizure test compared to nontransgenic mice. However, 5-HT6 receptor blockade had no affect on seizure threshold in either AD genotype, but did exhibit strain and ligand-dependent proconvulsant effects in naïve and otherwise healthy mice. Lastly, studies in Chapter 4 found that corneal kindled mice, which are a model of seizure development, exhibited DG-associated spatial pattern processing impairments. In vitro electrophysiology in acute hippocampal brain slices revealed DG granule cells in corneal kindled mice were hyperexcitable and had long-term potentiation deficits associated with DG-mediated cognitive dysfunction. Together, these results suggest that targeting disinhibition and aberrant hyperexcitability may be viable therapeutic targets for treating memory dysfunction in epilepsy. Ideally, new treatments for memory impairment should be both procognitive and anticonvulsant. |
