Elevations in extracellular potassium (K+e) accompany seizure-like events (SLEs), but elevated K+ may also participate in seizure cessation. The objective of this thesis was to investigate the possibility that K+ may undergo a pro- to anti-convulsant switch in the epileptic juvenile (postnatal day 17-21) rat hippocampus. Field recordings were performed in the CA1 pyramidal layer. SLEs and primary afterdischarges (PADs) were induced with 0.25 mM Mg/5 mM K+ perfusion or tetanic stimulation of the Schaffer collaterals respectively. In these seizure models, elevating [K+]e beyond 7.5 mM showed anticonvulsant properties. The addition of ZD7288, a blocker of the hyperpolarization activated nonspecific cationic current (Ih) and allowed SLEs to continue even in elevated [K+]e. This suggests that [K+]e switches from being pro- to anti-convulsant, in part due to an elevated [K+]e-induced potentiation of Ih. Ih likely contributes to this anticonvulsant behavior by decreasing membrane resistance and subsequently attenuating summation of incoming EPSPs.

Astrocytes, the major type of non-neuronal cells in the brain, play an important functional role in the brains extracellular potassium (K+) and pH homeostasis. Pathological brain states have been shown to cause astrocyte swelling. However, these volume changes have never before been verified to occur in response to physiological activity. In the present thesis, two-photon laser scanning microscopy was used to visualize real-time astrocyte volume changes in the stratum radiatum of the CA1 region of the hippocampus. Astrocyte somas and primary processes were observed to swell by 19.0±0.9% in response to a physiological (3 mM) increase in the concentration of extracellular K+. Astrocyte swelling was partially mediated by K+ influx through inwardly rectifying K+ channels (Kir), as their inhibition resulted in a significant decrease of the increased K+ induced astrocyte swelling (13.9±0.9%). In addition, the bicarbonate ion (HCO3-) was found to play a significant role in the increased K+ induced astrocyte swelling. The astrocyte swelling was significantly decreased when the influx of HCO3- was decreased in 1) a HCO3- free extracellular solution (5.4±0.7%), 2) in the presence of an extracellular carbonic anhydrase inhibitor (11.4±0.6% ), and 3) when the activity of the sodium-bicarbonate cotransporter (NBC) was blocked (8.3±0.7%) . Conversely, astrocytes were found to shrink by 7.7±0.5% in response to ã-Amino-butyric Acid (GABA) receptor activation. GABAA receptor mediated astrocyte shrinkage was significantly decreased to 5.0±0.6% when HCO3- efflux was reduced. Furthermore, in this thesis it was shown for the first time that astrocytes swell in response to neuronal stimulation (4.0±0.4%). This activity induced astrocyte swelling was significantly decreased to 1.5±0.2% in a HCO3- free extracellular solution. These astrocyte volume changes may have important implications for the regulation of brain activity under both physiological and pathological brain states.

Elevations in extracellular potassium (K+e) accompany seizure-like events (SLEs), but elevated K+ may also participate in seizure cessation. The objective of this thesis was to investigate the possibility that K+ may undergo a pro- to anti-convulsant switch in the epileptic juvenile (postnatal day 17-21) rat hippocampus. Field recordings were performed in the CA1 pyramidal layer. SLEs and primary afterdischarges (PADs) were induced with 0.25 mM Mg/5 mM K+ perfusion or tetanic stimulation of the Schaffer collaterals respectively. In these seizure models, elevating [K+]e beyond 7.5 mM showed anticonvulsant properties. The addition of ZD7288, a blocker of the hyperpolarization activated nonspecific cationic current (Ih) and allowed SLEs to continue even in elevated [K+]e. This suggests that [K+]e switches from being pro- to anti-convulsant, in part due to an elevated [K+]e-induced potentiation of Ih. Ih likely contributes to this anticonvulsant behavior by decreasing membrane resistance and subsequently attenuating summation of incoming EPSPs.

Astrocytes, the major type of non-neuronal cells in the brain, play an important functional role in the brains extracellular potassium (K+) and pH homeostasis. Pathological brain states have been shown to cause astrocyte swelling. However, these volume changes have never before been verified to occur in response to physiological activity. In the present thesis, two-photon laser scanning microscopy was used to visualize real-time astrocyte volume changes in the stratum radiatum of the CA1 region of the hippocampus. Astrocyte somas and primary processes were observed to swell by 19.0±0.9% in response to a physiological (3 mM) increase in the concentration of extracellular K+. Astrocyte swelling was partially mediated by K+ influx through inwardly rectifying K+ channels (Kir), as their inhibition resulted in a significant decrease of the increased K+ induced astrocyte swelling (13.9±0.9%). In addition, the bicarbonate ion (HCO3-) was found to play a significant role in the increased K+ induced astrocyte swelling. The astrocyte swelling was significantly decreased when the influx of HCO3- was decreased in 1) a HCO3- free extracellular solution (5.4±0.7%), 2) in the presence of an extracellular carbonic anhydrase inhibitor (11.4±0.6% ), and 3) when the activity of the sodium-bicarbonate cotransporter (NBC) was blocked (8.3±0.7%) . Conversely, astrocytes were found to shrink by 7.7±0.5% in response to ã-Amino-butyric Acid (GABA) receptor activation. GABAA receptor mediated astrocyte shrinkage was significantly decreased to 5.0±0.6% when HCO3- efflux was reduced. Furthermore, in this thesis it was shown for the first time that astrocytes swell in response to neuronal stimulation (4.0±0.4%). This activity induced astrocyte swelling was significantly decreased to 1.5±0.2% in a HCO3- free extracellular solution. These astrocyte volume changes may have important implications for the regulation of brain activity under both physiological and pathological brain states.

In isolated skeletal muscle arterioles, increasing transmural pressure causes an increase in constriction. This active myogenic response varies with age and fiber type. Increased transmural pressure activates both Ca2+-activated (KCa) potassium channels and voltage-dependent (Kv) potassium channels; these channels have a role in the negativefeedback pathways that modulate depolarization and myogenic constriction. We tested the hypothesis that increased KCa channel and Kv channel activity contribute to reduced myogenic responsiveness in skeletal muscle arterioles of aged rats. 1A arterioles were isolated from soleus, an oxidative muscle, and superficial gastrocnemius, a glycolytic muscle, of young (4 mos) and aged (24 mos) Fischer 344 rats. Myogenic responses were assessed by increasing intraluminal pressure (0-140 cm H2O) in increments of 20cm H2O. Vasoconstrictor response were determined in response to increasing concentrations of the KCa channel blocker, charybdotoxin (CTX; 10-10 to 10-7 M) and the Kv channel blocker, 4-Aminopyridine (4-AP; 10-5 to 10-2 M). To determine the role of potassium channels in modulating the myogenic response, cannulated arterioles from soleus and gastrocnemius were incubated with CTX (50 nM) and 4-AP (5mM) for 15 minutes prior to evaluation of the myogenic response. Increased Kv channel activity contributes to reduced myogenic constriction in soleus and gastrocnemius muscle arterioles from aged rats. In soleus muscle arterioles, KCa channel activity opposes myogenic tone in young but not old rats. In gastrocnemius muscle arterioles, treatment with CTX did not eliminate age-related differences in the myogenic response, and the KCa channel contribution to myogenic tone was, in fact, greater arterioles from young as compared to old rats. Kv channels contribute to greater myogenic constriction in soleus arterioles, KCa channels appear to be more active in gastrocnemius muscle arterioles as compared to soleus muscle arterioles. Therefore Kv and KCa channels are tonically active in skeletal muscle arterioles, contributing to a hyperpolarizing force that opposes myogenic constriction. Furthermore, increased Kv channel activity contributes to the age-related reduction of myogenic constriction in soleus and gastrocnemius muscle arterioles.

Thesis (Ph. D.)--University of Pittsburgh, 1915. / Vita.

Thesis (Ph. D.)--Lehigh University, 2001. / Includes bibliographical references and vita.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 120-134). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph.D.)--Ohio University, November, 2009. / Release of full electronic text on OhioLINK has been delayed until December 1, 2014. Title from PDF t.p. Includes bibliographical references.

Thesis (M.S.) in Zoology--University of Maine, 2009. / Includes vita. Includes bibliographical references (leaves 60-73).