Plasticity of synapses is not static across the lifespan. As the brain matures and ages, the ability of neurons to undergo structural and functional change becomes more limited. Further, there are a number of modulatory factors that influence the expression of synaptic plasticity. Here, three approaches were taken to examine and manipulate plasticity in the auditory thalamocortical system of rats. Using an in vivo preparation, long-term potentiation (LTP) and paired pulse (PP) responses were used as measures of long- and short-term plasticity, respectively. First, the effect of intracortical zinc application in the primary auditory cortex (A1) on LTP was examined. Following theta burst stimulation (TBS) of the medial geniculate nucleus (MGN), juvenile and middle-age rats, but not young adults, showed greater levels of LTP with zinc application relative to age-matched control animals. Next, PP responses were examined between rats reared in unaltered acoustic conditions and those reared in continuous white noise (WN) from postnatal day (PD) 5 to PD 50-60 (i.e., subjected to patterned sound deprivation). Rats reared in WN demonstrated less PP depression relative to controls, indicating that WN rearing alters short-term thalamocortical synaptic responses. Furthermore, control males showed no change in PP response following LTP induction, indicating a postsynaptic locus of LTP, whereas increased PP depression following LTP induction was seen in WN animals, suggestive of a presynaptic involvement in LTP. Finally, differences in plasticity between male and female rats were investigated, and the result of early WN exposure on both sexes was examined. Males and females did not show consistent differences in LTP expression; however WN exposure appeared to affect LTP of females less than their male counterparts. PP responses were then compared between WN-reared males and females, and no difference was found. This indicates that short-term plastic properties of auditory thalamocortical synapses between the sexes do not differ, even though plasticity on a longer time scale following sensory deprivation does indicate some difference. Together, the experiments summarized here identify some of the important factors that contribute to the regulation of short- and long-term synaptic plasticity in the central auditory system of the mammalian brain. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2012-10-30 16:01:28.796

Excitatory synaptic transmission and plasticity mediated by glutamate receptors are important for many brain functions, including learning and memory. Various molecular and cellular models have been established to study multiple forms of synaptic plasticity that coexist in the hippocampal CA1 region. Metabotropic glutamate receptor-dependent long-term depression (mGluR-dependent LTD) is a form of long lasting synaptic plasticity thought to play critical roles in diverse physiological and pathological processes. The GluR2 subunit of AMPA receptors has been a focus of neuroscience research over the last decade due to its important roles in endocytic trafficking and Ca2+ permeation in many forms of activity-dependent synaptic plasticity and homeostatic plasticity. However, the underlying mechanisms of mGluR-dependent LTD and the possible involvement of GluR2 in this form of plasticity remain unknown. In this project, I utilized GluR2 knockout (KO) mice and tested the requirement of GluR2 in multiple forms of hippocampal synaptic plasticity at different developmental stages. The results showed that although GluR2 is dispensable for long lasting synaptic plasticity in juvenile mice, it is essential for the expression of mGluR-dependent LTD in adult animals. Next, I examined the involvement of a number of GluR2-specific functions in mGluR-dependent LTD and found that GluR2 N-terminal interaction with the cell adhesion molecule N-cadherin is a key process required for GluR2 to regulate the expression of mGluR-dependent LTD. Furthermore, using a combination of approaches including electrophysiology, biochemical assays, and virus-mediated expression of several mutant GluR2 constructs, I identified a signaling cascade involving N-cadherin/β-catenin complex, Rac1 Rho GTPase, LIM-kinase 1 and cofilin, through which GluR2 exerts its effect on actin regulation and mGluR-dependent LTD. Importantly, the impaired LTD in GluR2 KO mice can be fully rescued by manipulating GluR2-N-cadherin N-terminus interaction or cofilin-mediated actin reorganization. Lastly, I showed that this signaling cascade also plays a critical role in the regulation of dendritic spine plasticity during mGluR-dependent LTD. Together, these results reveal a novel signaling process by which GluR2 regulates long lasting synaptic plasticity and provide insights into how functional and structural plasticity are coordinated in the mammalian central nervous system.

Excitatory synaptic transmission and plasticity mediated by glutamate receptors are important for many brain functions, including learning and memory. Various molecular and cellular models have been established to study multiple forms of synaptic plasticity that coexist in the hippocampal CA1 region. Metabotropic glutamate receptor-dependent long-term depression (mGluR-dependent LTD) is a form of long lasting synaptic plasticity thought to play critical roles in diverse physiological and pathological processes. The GluR2 subunit of AMPA receptors has been a focus of neuroscience research over the last decade due to its important roles in endocytic trafficking and Ca2+ permeation in many forms of activity-dependent synaptic plasticity and homeostatic plasticity. However, the underlying mechanisms of mGluR-dependent LTD and the possible involvement of GluR2 in this form of plasticity remain unknown. In this project, I utilized GluR2 knockout (KO) mice and tested the requirement of GluR2 in multiple forms of hippocampal synaptic plasticity at different developmental stages. The results showed that although GluR2 is dispensable for long lasting synaptic plasticity in juvenile mice, it is essential for the expression of mGluR-dependent LTD in adult animals. Next, I examined the involvement of a number of GluR2-specific functions in mGluR-dependent LTD and found that GluR2 N-terminal interaction with the cell adhesion molecule N-cadherin is a key process required for GluR2 to regulate the expression of mGluR-dependent LTD. Furthermore, using a combination of approaches including electrophysiology, biochemical assays, and virus-mediated expression of several mutant GluR2 constructs, I identified a signaling cascade involving N-cadherin/β-catenin complex, Rac1 Rho GTPase, LIM-kinase 1 and cofilin, through which GluR2 exerts its effect on actin regulation and mGluR-dependent LTD. Importantly, the impaired LTD in GluR2 KO mice can be fully rescued by manipulating GluR2-N-cadherin N-terminus interaction or cofilin-mediated actin reorganization. Lastly, I showed that this signaling cascade also plays a critical role in the regulation of dendritic spine plasticity during mGluR-dependent LTD. Together, these results reveal a novel signaling process by which GluR2 regulates long lasting synaptic plasticity and provide insights into how functional and structural plasticity are coordinated in the mammalian central nervous system.

Synaptic alterations in the nucleus accumbens (NAc) are crucial for the aberrant reward-associated learning that forms the foundation of drug dependence. Glutamatergic synaptic plasticity in the NAc has been implicated in several behavioral responses to psychomotor stimulating agents, such as cocaine and amphetamine, yet no studies, at present, have investigated its modulation by ethanol. We demonstrated that both in vitro and in vivo ethanol treatment significantly disrupts normal synaptic functioning in medium spiny neurons (MSNs) of the NAc shell. Utilizing whole-cell voltage clamp recording techniques, synaptic conditioning (low frequency stimulation with concurrent postsynaptic depolarization) reliably depressed (NAc-LTD) AMPA-mediated excitatory postsynaptic currents (EPSCs). Acute ethanol exposure inhibited the depression of AMPA EPSCs differentially with increasing concentrations, but this inhibitory action of ethanol was reversed by a D1-like dopamine receptor agonist. When examined 24 hours following a single bout of in vivo chronic intermittent ethanol (CIE) vapor exposure, NAc-LTD was absent and instead synaptic potentiation (LTP) was reliably observed. We further investigated CIE-induced modulation of NAc-LTD by distinguishing between the two subpopulations of MSNs in the NAc, D1 receptor-expressing (D1+) and D2 receptor-expressing (D1-). We determined that NAc-LTD is expressed solely in D1+ but not D1- MSNs. In addition, 24 hours following a repeated regimen of in vivo CIE exposure NAc-LTD is completely occluded in D1+ MSNs, while D1- MSNs are able to express LTD. Complete recovery of normal synaptic plasticity expression in both D1+ and D1- MSNs does not occur until two weeks of withdrawal from CIE vapor exposure. To our knowledge, this is the first demonstration of a reversal in the cell type-specificity of synaptic plasticity in the NAc shell, as well as, the gradual recovery of the pre-drug exposure plasticity state following extended withdrawal. This study suggests that NAc-LTD is cell type-specific and highly sensitive to both acute and chronic ethanol exposure. We believe these observations also highlight the adaptability of NAc MSNs to the effects of long-term ethanol exposure. A change in these synaptic processes may constitute a neural adaptation that contributes to the induction and/or expression of alcohol dependence. / text

One of the central questions of neuroscience research has been how the cellular and molecular components of the brain give rise to complex behaviours. Three major breakthroughs from the past sixty years have made the study of learning and memory central to our understanding of how the brain works. First, the psychologist Donald Hebb proposed that information storage in the brain could occur through the strengthening of the connections between neurons if the strengthening were restricted to neurons that were co-active (Hebb, 1949). Second, Milner and Scoville (1957) showed that the hippocampus is required for the acquisition of new long-term memories for consciously accessible, or declarative, information. Third, Bliss and Lømo (1973) demonstrated that the synapses between neurons in the dentate gyrus of the hippocampus could indeed be potentiated in an activity-dependent manner. Long-term potentiation (LTP) of the glutamatergic synapses in area CA1, the primary output of the hippocampus, has since become the leading model of synaptic plasticity due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals, and its robust pathway specificity. Using whole-cell recording in hippocampal slices from adult rats, I find that the efficacy of synaptic transmission from CA3 to CA1 can in fact be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, I show that the induction of GABAergic plasticity at feedforward inhibitory inputs in CA1 results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials which is dependent on NMDAR activation and is pathway specific. The sharing of these fundamental properties with classic LTP suggests the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.

One of the central questions of neuroscience research has been how the cellular and molecular components of the brain give rise to complex behaviours. Three major breakthroughs from the past sixty years have made the study of learning and memory central to our understanding of how the brain works. First, the psychologist Donald Hebb proposed that information storage in the brain could occur through the strengthening of the connections between neurons if the strengthening were restricted to neurons that were co-active (Hebb, 1949). Second, Milner and Scoville (1957) showed that the hippocampus is required for the acquisition of new long-term memories for consciously accessible, or declarative, information. Third, Bliss and Lømo (1973) demonstrated that the synapses between neurons in the dentate gyrus of the hippocampus could indeed be potentiated in an activity-dependent manner. Long-term potentiation (LTP) of the glutamatergic synapses in area CA1, the primary output of the hippocampus, has since become the leading model of synaptic plasticity due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals, and its robust pathway specificity. Using whole-cell recording in hippocampal slices from adult rats, I find that the efficacy of synaptic transmission from CA3 to CA1 can in fact be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, I show that the induction of GABAergic plasticity at feedforward inhibitory inputs in CA1 results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials which is dependent on NMDAR activation and is pathway specific. The sharing of these fundamental properties with classic LTP suggests the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.

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On short timescales, the brain represents, transmits, and processes information through the electrical activity of its neurons. On long timescales, the brain stores information in the strength of the synaptic connections between its neurons. This thesis examines the surprising implications of two separate, well documented microscopic processes — the stochastic gating of ion channels and the plasticity of dendritic spines — for neural information processing and storage. Electrical activity in neurons is mediated by many small membrane proteins called ion channels. Although single ion channels are known to open and close stochastically, the macroscopic behaviour of populations of ion channels are often approximated as deterministic. This is based on the assumption that the intrinsic noise introduced by stochastic ion channel gating is so weak as to be negligible. In this study we take advantage of newly developed efficient computer simulation methods to examine cases where this assumption breaks down. We find that ion channel noise can mediate spontaneous action potential firing in small nerve fibres, and explore its possible implications for neuropathic pain disorders of peripheral nerves. We then characterise the magnitude of ion channel noise for single neurons in the central nervous system, and demonstrate through simulation that channel noise is sufficient to corrupt synaptic integration, spike timing and spike reliability in dendritic neurons. The second topic concerns neural information storage. Learning and memory in the brain has long been believed to be mediated by changes in the strengths of synaptic connections between neurons — a phenomenon termed synaptic plasticity. Most excitatory synapses in the brain are hosted on small membrane structures called dendritic spines, and plasticity of these synapses is dependent on calcium concentration changes within the dendritic spine. In the last decade, it has become clear that spines are highly dynamic structures that appear and disappear, and can shrink and enlarge on rapid timescales. It is also clear that this spine structural plasticity is intimately linked to synaptic plasticity. Small spines host weak synapses, and large spines host strong synapses. Because spine size is one factor which determines synaptic calcium concentration, it is likely that spine structural plasticity influences the rules of synaptic plasticity. We theoretically study the consequences of this observation, and find that different spine-size to synaptic-strength relationships can lead to qualitative differences in long-term synaptic strength dynamics and information storage. This novel theory unifies much existing disparate data, including the unimodal distribution of synaptic strength, the saturation of synaptic plasticity, and the stability of strong synapses.

Learning and memory storage is believed to occur at the synaptic connections between neurons. During the last decades it has become clear that synapses are plastic at short and long time scales. Furthermore, experiments have shown that short and long-term synaptic plasticity interact. It remains unclear, however, how is this interaction implemented and how does it impact information processing and learning in cortical networks. In this thesis I present results on the mechanisms and function of this interaction. On the mechanistic level this form of plasticity is known to rely on a presynaptic coincidence mechanism, which requires the activation of presynaptic NMDA receptors (preNMDARs). In a collaborative effort I used mathematical modeling combined with experiments to show that preNMDARs reroute information flow in local circuits during high-frequency firing, by specifically impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells. In order to accurately characterize how do preNMDARs regulate the release machinery, I developed a probabilistic inference framework that provides a distribution over the relevant parameter space, rather than simple point estimates. This approach allowed me to propose better experimental protocols for short-term plasticity inference and to reveal connection-specific synaptic dynamics in the layer-5 canonical microcircuit. This framework was then extended to infer short-term plasticity from preNMDAR pharmacological blockade data. The results show that preNMDARs up-regulate the baseline release probability and the depression time-constant, which is consistent with experimental analysis and that their impact appears to be connection-specific. I also show that a preNMDAR phenomenological model captures the frequency-dependence activation of preNMDARs. Furthermore, preNMDARs increase the signal-to-noise ratio of synaptic responses. These results show that preNMDARs specifically up-regulate high frequency synaptic information transmission. Finally, I introduce a pre- and postsynaptic unified mathematical model of spike-timing- dependent synaptic plasticity. I show that this unified model captures a wide range of short-term and long-term synaptic plasticity data. Functionally, I demonstrate that this segregation into pre- and postsynaptic factors explains some observations on receptive field development and enable rapid relearning of previously stored information, in keeping with Ebbinghaus’s memory savings theory.