The balance between excitatory and inhibitory synaptic transmission within and across neurons in active networks is crucial for cortical function and may allow for rapid transitions between stable network states. GABAergic interneurons mediate the majority of inhibitory transmission in the cortex, and therefore contribute to the global balance of activity in neuronal networks. Disruption in the network balance due to impaired inhibition has been implicated in several neuropsychiatric diseases (Marin 2012). Both schizophrenia and autism are two highly heritable cognitive disorders with complex genetic aetiologies but overlapping behavioural phenotypes that share common imbalances in neuronal network activity (Gao & Penzes 2015). An increasing body of evidence suggests that functional abnormalities in a particular group of cortical GABAergic interneurons expressing the calcium-binding protein parvalbumin (PV) are involved in the pathology of these disorders (Marin 2012). As deficits in this neuronal population have been linked to these disorders it could be useful to target them and increase their activity. A conserved feature in PV cells is their unusually low input resistance compared to other neuronal populations. This feature is regulated by the expression of leak K+ channels, believed to be mediated in part by TASK and TREK subfamily two-pore K+ channels (Goldberg et al. 2011). The selective blockade of specific leak K+ channels could therefore be applied to increase the activity of PV cells. In this thesis, specific TASK-1/3 and TREK-1 channel blockers were applied in cortical mouse slices in an attempt to increase the output of PV cells. The blockade of either channel did not successfully increase the amplitude of PV cell-evoked inhibitory postsynaptic currents (IPSCs) onto principal cells. However, while the blockade of TASK-1/3 channels failed to depolarise the membrane or alter the input resistance, the blockade of TREK-1 channels resulted in a small but significant depolarisation of the membrane potential in PV cells. Interestingly, TREK-1 channel blockade also increased action potential firing of PV cells in response to given current stimuli, suggesting that TREK-1 could be a useful target for PV cell modulation. These results demonstrate for the first time the functional effects of using specific two-pore K+ channel blockers in PV cells. Furthermore, these data provide electrophysiological evidence against the functional expression of TASK-1/3 in PV cells. It could therefore be interesting to further characterise the precise subtypes of leak K+ channels responsible for their low resistivity. This would help to classify the key contributors of the background K+ conductances present in PV cells in addition to finding suitable targets to increase their activity.

Large parts of the cortex and the thalamus project into the striatum,which serves as the input stage of the basal ganglia. Information isintegrated in the striatal neural network and then passed on, via themedium spiny (MS) projection neurons, to the output stages of thebasal ganglia. In addition to the MS neurons there are also severaltypes of interneurons in the striatum, such as the fast spiking (FS)interneurons. I focused my research on the FS neurons, which formstrong inhibitory synapses onto the MS neurons. These striatal FSneurons are sparsely connected by electrical synapses (gap junctions),which are commonly presumed to synchronise their activity.Computational modelling with the GENESIS simulator was used toinvestigate the effect of gap junctions on a network of synapticallydriven striatal FS neurons. The simulations predicted a reduction infiring frequency dependent on the correlation between synaptic inputsto the neighbouring neurons, but only a slight synchronisation. Thegap junction effects on modelled FS neurons showing sub-thresholdoscillations and stuttering behaviour confirm these results andfurther indicate that hyperpolarising inputs might regulate the onsetof stuttering.The interactions between MS and FS neurons were investigated byincluding a computer model of the MS neuron. The hypothesis was thatdistal GABAergic input would lower the amplitude of back propagatingaction potentials, thereby reducing the calcium influx in thedendrites. The model verified this and further predicted that proximalGABAergic input controls spike timing, but not the amplitude ofdendritic calcium influx after initiation.Connecting models of neurons written in different simulators intonetworks raised technical problems which were resolved by integratingthe simulators within the MUSIC framework. This thesis discusses theissues encountered by using this implementation and gives instructionsfor modifying MOOSE scripts to use MUSIC and provides guidelines forachieving compatibility between MUSIC and other simulators.This work sheds light on the interactions between striatal FS and MSneurons. The quantitative results presented could be used to developa large scale striatal network model in the future, which would beapplicable to both the healthy and pathological striatum. / QC 20100720

<p>Interval timing, defined as timing and time perception in the seconds-to-minutes range, is a higher-order cognitive function that has been shown to be critically dependent upon cortico-striatal circuits in the brain. However, our understanding of how different neuronal subtypes within these circuits cooperate to subserve interval timing remains elusive. The present study was designed to investigate this issue by focusing on the spike waveforms of neurons and their synchronous firing patterns with local field potentials (LFPs) recorded from cortico-striatal circuits while rats were performing two standard interval-timing tasks. Experiment 1 demonstrated that neurons in cortico-striatal circuits can be classified into 4 different clusters based on their distinct spike waveforms and behavioral correlates. These distinct neuronal populations were shown to be differentially involved in timing and reward processing. More importantly, the LFP-spike synchrony data suggested that neurons in 1 particular cluster were putative fast-spiking interneurons (FSIs) in the striatum and these neurons responded to both timing and reward processing. Experiment 2 reported electrophysiological data that were similar with previous findings, but identified a different cluster of striatal neurons - putative tonically-active neurons (TANs), revealed by their distinct spike waveforms and special firing patterns during the acquisition of the task. These firing patterns of FSIs and TANs were in contrast with potential striatal medium-spiny neurons (MSNs) that preferentially responded to temporal processing in the current study. Experiment 3 further investigated the proposal that interval timing is subserved by cortico-striatal circuits by using microstimulation. The findings revealed a stimulation frequency-dependent "stop" or "reset" response pattern in rats receiving microstimulation in either the cortex or the striatum during the performance of the timing task. Taken together, the current findings further support that interval timing is represented in cortico-striatal networks that involve multiple types of interneurons (e.g., FSIs and TANs) functionally connected with the principal projection neurons (i.e., MSNs) in the dorsal striatum. When specific components of these complex networks are electrically stimulated, the ongoing timing processes are temporarily "stopped" or "reset" depending on the properties of the stimulation.</p> / Dissertation