Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.

Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.

Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.

Oxytocin has established roles in parturition and lactation, but can also be released in response to non-reproductive stimuli, such as hyperosmolarity and stress. As a majority of appetite regulating peptides activate the hypothalamo-pituitary-adrenal stress axis, and oxytocin is also a stress hormone in the rat, it was hypothesized that the oxytocin system in the neurohypophysial axis could be a target for appetite-regulating peptides of central and peripheral origin. The effects of central administration of neuropeptide Y (NPY; a central orexigenic peptide and a central and peripheral neurotransmitter co-released with noradrenaline; n=5 rats) and systemic administration of secretin (a peripheral gut peptide belonging to the family of brain-gut peptides; n=26) and leptin (a peripheral anorexigenic peptide from adipose tissue; n=23) on the electrical activity of SON oxytocin neurones in vivo were studied in urethane-anaesthetized female rats with extracellular recording. Effects were compared with the excitatory responses to cholecystokinin (CCK; a peripheral anorexigenic gut peptide; n=45). Influences of fasting and pregnancy and effects of these peptides on the activity of SON vasopressin neurones were also studied. Results: (1) All the central and peripheral appetite peptides tested increased the electrical activity of SON oxytocin neurones. (a) NPY: Basal firing rate of 3.5 ± 1.05 (mean ± s.e.m) spikes/s was increased by 1 ± 0.45 spikes/s 1min after NPY (basal vs 0-10min post-NPY: P=0.03, paired t-test; n=5). (b) Secretin: Basal rate of 4.1 ± 0.4 spikes/s was increased by 1.7 ± 0.2 spikes/s 2.5min after secretin (basal vs 0-10min post-secretin: P<0.001, paired t-test; n=26). (c) Leptin: Basal rate of 3.4 ± 0.4 spikes/s was increased by 0.4 ± 0.08 spikes/s 1.5min after leptin (basal vs 0-10min post-leptin: P=0.01, paired t-test; n=23). (d) CCK: Basal rate of 3.6 ± 0.3 spikes/s was increased by 1.1 ± 0.15 spikes/s 1min after CCK (basal vs 0-10min post- CCK: P<0.001, Wilcoxon signed rank test; n=45). (2) Secretin induced excitatory responses were greater than to other peptides (P<0.001, Kruskal-Wallis one-way ANOVA on ranks). (3) Secretin dose-dependently increased SON oxytocin neurone electrical activity and peripheral oxytocin release in anaesthetized rats. (4) Intracerebroventricular infusion and microdialysis studies with benoxathian (α1 adrenergic antagonist) revealed that secretininduced excitation of SON oxytocin and vasopressin neurones involves central excitatory noradrenergic pathways. (5) Fasting for 18h did not alter the excitation of SON oxytocin neurones induced by secretin, CCK and leptin. (6) The pathway leading to excitation of oxytocin neurones by CCK was not influenced by prior leptin administration. (7) SON oxytocin neurones were responsive to leptin during late pregnancy. (8) NPY-induced excitation of oxytocin neurones was intact in anaesthetised late pregnant rats, contrasting with attenuated oxytocin secretory responses observed previously in conscious rats. (9) Systemic NPY excited SON oxytocin neurones. (10) Systemic CCK administration either inhibited (77%) or did not affect (23%) SON vasopressin neurones, while leptin had no significant effect, and responses to secretin were predominantly excitatory (67%). Systemic NPY inhibited vasopressin neurones, but central NPY was ineffective. Conclusion: Appetite peptides target SON oxytocin neurones. Postprandially released secretin and leptin might, like CCK, induce peripheral oxytocin release, so as to regulate water and electrolyte homeostasis, which is inevitably disturbed during feeding. Any central release of oxytocin induced by these peptides, might regulate feeding behaviour and satiety. Oxytocin neurone excitation induced by NPY may be relevant during stress responses.

Recent approaches in depression therapeutics include triple reuptake inhibitors, drugs that target three monoamine systems. Using in vivo electrophysiological and microdialysis techniques, the effects of 2- and 14-day treatments of escitalopram, nomifensine and the co-administration of these two drugs (TRI) were examined in male Sprague-Dawley rats. Short- and long-term TRI administration decreased NE firing and had no effect on DA neurons. Normal 5-HT firing rates were maintained after 2-day TRI administration compared to the robust inhibitory action of selective serotonin reuptake inhibitors (SSRIs). Escitalopram treatment enhanced the tonic activation of the 5-HT1A receptors given the increase in firing observed following WAY100635 administration. Nomifensine treatment enhanced tonic activation of the α2–adrenoceptors following idazoxan administration. TRI treatment caused a robust increase in extracellular DA levels that was in part mediated by a serotonergic contribution. Therapeutic effects of the drugs examined in this study may be due to the enhancement of 5-HT, NE and/or DA neurotransmission.

Use-dependent long-term plasticity in synaptic connections represents the cellular substrate for learning and memory. The hippocampus is the most thoroughly investigated brain area for long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) are both well characterized in glutamatergic excitatory connections between hippocampal principal cells in vitro and in vivo. An increasing number of studies based on acute brain slice preparations report LTP and LTD in excitatory synapses onto postsynaptic hippocampal GABAergic inhibitory interneurons. However, a systematic study of activity-induced long-term plasticity in excitatory synaptic connections to inhibitory GABAergic interneurons in vivo is missing. To determine whether LTP and LTD occur in excitatory synaptic connections to the hippocampal CA1 area GABAergic interneurons types in intact brain, I have used juxtacellular recording to measure synaptically evoked short-delay postsynaptic action potential probability in identified CA1 neurons in the urethane-anaesthetized rats. Plasticity in excitatory synaptic connections to CA1 cell types was measured as a change of afferent pathway stimulation-evoked postsynaptic spike probability and delay. In the study only experiments with monosynaptic-like short-delay (range 3-12 ms) postsynaptic spikes phase-locked to afferent stimulation were used. Afferent fibres were stimulated from the CA1 area of the hippocampus at the contralateral (left) side to avoid simultaneous monosynaptic activation of GABAergic fibres and to exclude antidromic spikes in recorded CA1 cells (in right hemisphere). Plasticity in pathways was tested using theta-burst high-frequency stimulation (TBS, 100 pulses), which is one of the most common synaptic plasticity induction protocols in acute brain slice studies. I discovered that TBS elicited permanent potentiation in single shock-evoked postsynaptic spike probability with shortening or no change in evoked spike latency in various postsynaptic neuron types including three identified pyramidal cells and parvalbumin-expressing (PV&plus;) interneurons. Most fast-spiking PV+ cells showed LTP including an axo-axonic cell and one bistratified cell, whereas two identified basket cells exhibited LTD in similar experimental conditions. In addition, I discovered diverse plasticity in non-fast spiking interneurons, reporting LTP in an ivy cell, and LTD in three incompletely identified regular-spiking CA1 interneurons. I report that the underlying brain state, defined as theta oscillation (3-6 Hz) or non-theta in local field potential, failed to explain whether LTP, LTD or no plasticity was generated in interneurons. The results show that activity-induced potentiation and depression similar to LTP and LTD also occur in excitatory synaptic pathways to various CA1 interneurons types in vivo. I propose that long-term plasticity in excitatory connections to inhibitory interneurons may be take place in learning and memory processes in the hippocampus.

Recent approaches in depression therapeutics include triple reuptake inhibitors, drugs that target three monoamine systems. Using in vivo electrophysiological and microdialysis techniques, the effects of 2- and 14-day treatments of escitalopram, nomifensine and the co-administration of these two drugs (TRI) were examined in male Sprague-Dawley rats. Short- and long-term TRI administration decreased NE firing and had no effect on DA neurons. Normal 5-HT firing rates were maintained after 2-day TRI administration compared to the robust inhibitory action of selective serotonin reuptake inhibitors (SSRIs). Escitalopram treatment enhanced the tonic activation of the 5-HT1A receptors given the increase in firing observed following WAY100635 administration. Nomifensine treatment enhanced tonic activation of the α2–adrenoceptors following idazoxan administration. TRI treatment caused a robust increase in extracellular DA levels that was in part mediated by a serotonergic contribution. Therapeutic effects of the drugs examined in this study may be due to the enhancement of 5-HT, NE and/or DA neurotransmission.

Recent approaches in depression therapeutics include triple reuptake inhibitors, drugs that target three monoamine systems. Using in vivo electrophysiological and microdialysis techniques, the effects of 2- and 14-day treatments of escitalopram, nomifensine and the co-administration of these two drugs (TRI) were examined in male Sprague-Dawley rats. Short- and long-term TRI administration decreased NE firing and had no effect on DA neurons. Normal 5-HT firing rates were maintained after 2-day TRI administration compared to the robust inhibitory action of selective serotonin reuptake inhibitors (SSRIs). Escitalopram treatment enhanced the tonic activation of the 5-HT1A receptors given the increase in firing observed following WAY100635 administration. Nomifensine treatment enhanced tonic activation of the α2–adrenoceptors following idazoxan administration. TRI treatment caused a robust increase in extracellular DA levels that was in part mediated by a serotonergic contribution. Therapeutic effects of the drugs examined in this study may be due to the enhancement of 5-HT, NE and/or DA neurotransmission.

Background: A single infusion of ketamine has rapid antidepressant properties, although the drawback is a lack of sustained effect. A previous study showed a rapid enhancement (within 2 hours) in ventral tegmental area (VTA) dopamine (DA) neuron population and locus coeruleus (LC) norepinephrine (NE) firing and bursting activity following a single ketamine administration. The current study investigated whether these changes are present 24 hours after a single administration and if they are maintained with repeated administration. Additionally, we examined dorsal raphe nucleus (DRN) serotonin (5-HT) neurons to assess the effects of single and repeated ketamine administration on these neurons. Methods: Ketamine (10 mg/kg, i.p.) was administered to male Sprague Dawley rats once or repeatedly (3 times/week) for 2 weeks. After single and repeated administration of ketamine, electrophysiological recordings were done in the VTA, LC and DRN in anesthetized rats, 24 hrs, 3 or 7 days post-administration. Spike frequency, bursting, and for VTA neurons, spontaneously active neurons/trajectory were assessed. Results: In the VTA, LC and DRN, 24 hrs after ketamine was injected acutely there was no significant difference between controls and treated animals in all parameters assessed. However, after repeated administration, there was an increase in bursting and number of spontaneously discharging neurons per tract of VTA DA neurons as well as an increase in frequency of discharge of LC NE neurons. While the increased number of spontaneously discharging neurons per tract had dissipated after 3 days, the enhanced bursting was still present but dissipated after 7 days. As for LC NE neurons, the increased frequency of discharge was no longer present after 3 days. No significant differences in the firing of DRN 5-HT neurons were observed between controls and treated animals even after ketamine was administered repeatedly. Conclusion: These results indicate that repeated but not acute administration of ketamine maintained the increase in population activity of DA neurons and firing activity of NE neurons.

As both the major input and output of the hippocampal formation, the entorhinal cortex (EC) occupies a pivotal position in the medial temporal lobe. The discovery of grid cells in the medial entorhinal cortex (mEC) has led to this region being widely implicated in spatial information processing. Importantly, the EC is also the first area affected by dementia pathology, with neurons appearing particularly susceptible to degeneration. Despite this, little is known about how pathology affects the functional output of mEC neurons, either in their ability to coordinate firing to produce network oscillations, or to represent information regarding the external environment. This thesis will use electrophysiological techniques to examine how dementia pathology contributes to the breakdown of mEC neuronal networks using the rTg4510 mouse model of tauopathy. The first 2 results chapters will show how the anatomical organisation along the dorso-ventral axis of the mEC has profound influence on the network activity that can be observed both in brain slices and awake-behaving mice. It will further show how deficits in network activity in rTg4510 mice occur differentially across this axis, with dorsal mEC appearing more vulnerable to changes in oscillatory function than ventral. The third results chapter will begin to explore the relationship between global network activity and the external environment, showing that rTg4510 mice display clear deficits in the relationship between oscillation properties and locomotor activity. Finally, the underlying basis for these changes will be examined, through the recording of single-unit activity in these mice. It will show a decreased tendency for mEC neurons to display firing rates modulated by running speed, as well as an almost complete breakdown of grid cell periodicity after periods of tau overexpression. Understanding how dementia pathology produces changes to neuronal function and ultimately cognition is key for understanding and treating the disease. This thesis will therefore provide novel insights into the dysfunction of the EC during dementia pathology.