Convergent metabotropic signalling pathways inhibit SK channels to promote synaptic plasticity in the hippocampus

Hebbian synaptic plasticity at hippocampal Schaffer collateral synapses is tightly regulated by postsynaptic SK channels that restrict NMDA receptor activity. SK channels are themselves modulated by G-protein-coupled signalling pathways, but it is not clear under what conditions these are activated to enable synaptic plasticity. Here, we show that muscarinic M1 receptor (M1R) and type 1 metabotropic glutamate receptor (mGluR1) signalling pathways, which are known to inhibit SK channels and thereby disinhibit NMDA receptors, converge to facilitate spine calcium transients during the induction of long-term potentiation (LTP) at hippocampal Schaffer collateral synapses onto CA1 pyramidal neurons of male rats. Furthermore, mGluR1 activation is required for LTP induced by reactivated place cell firing patterns that occur in sharp wave ripple events during rest or sleep. In contrast, M1R activation is required for LTP induced by place cell firing patterns during exploration. Thus, we describe a common mechanism that enables synaptic plasticity during both encoding and consolidation of memories within hippocampal circuits

Pre-reproductive parental enriching experiences influence progeny’s developmental trajectories

While the positive effects of environmental enrichment (EE) applied after weaning, in adulthood, during aging, or even in the presence of brain damage have been widely described, the transgenerational effects of pre-reproductive EE have been less examined. And yet, this issue is remarkable given that parental environmental experience may imprint offspring's phenotype over generations through many epigenetic processes. Interactions between individual and environment take place lifelong even before conception. In fact, the environment pre-reproductively experienced by the mother and/or the father exerts a substantial impact on neural development and motor and cognitive performances of the offspring, even if not directly exposed to social, cognitive, physical and/or motor enrichment. Furthermore, pre-reproductive parental enrichment exerts a transgenerational impact on coping response to stress as well as on the social behavior of the offspring. Among the effects of pre-reproductive parental EE, a potentiation of the maternal care and a decrease in global methylation levels in the frontal cortex and hippocampus of the progeny have been described. Finally, pre-reproductive EE modifies different pathways of neuromodulation in the brain of the offspring (involving brain-derived neurotrophic factor, oxytocin and glucocorticoid receptors). The present review highlights the importance of pre-reproductive parental enrichment in altering the performances not only of animals directly experiencing it, but also of their progeny, thus opening the way to new hypotheses on the inheritance mechanisms of behavioral trait

Cognitive Impairment and Aberrant Plasticity in the Kindling Model of Epilepsy

Epilepsy is a neurological disorder that affects approximately 1% of the population worldwide. Although motor seizures are the best known feature of epilepsy, many patients also experience severe interictal (between-seizure) behavioral and cognitive comorbidities that have a greater negative influence on quality of life than seizure control or frequency. To study the characteristics of these interictal comorbidities and the neural mechanisms that underlie them, I use the kindling model of epilepsy. Kindling refers to the brief electrical stimulation of a discrete brain site that produces a gradual and permanent increase in the severity of elicited seizure activity. The repeated seizures associated with kindling induce robust structural and functional plasticity that appears to be primarily aberrant. Importantly, the aberrant plasticity evoked by repeated seizures is thought to contribute to the pathophysiology of epilepsy and its associated behavioral and cognitive comorbidities. Unfortunately, the relationship between aberrant plasticity and cognition dysfunction following repeated seizures remains poorly understood. The aim of this dissertation is to gain a better understanding of the effects of repeated convulsions on aberrant neural plasticity and interictal behavior. In Chapter 2, I will examine the effect of short- and long-term amygdala kindling on amygdala- and hippocampal-dependent forms of operant fear conditioning. To evaluate whether kindling alters neural circuits important in memory, I will analyze post-mortem measures of neural activity following the retrieval of fearful memories. In Chapter 3, I will evaluate whether deficits in operant fear learning and memory are a general consequence of convulsions induced by kindling stimulations or whether these deficits occur following kindling of specific brain regions. To evaluate whether aberrant plasticity following kindling of different brain regions contributes to learning and memory deficits, I will make post-mortem examinations of the inhibitory neurotransmitter neuropeptide Y and its Y2 receptor. In Chapter 4, I will investigate the relationship between hippocampal neurogenesis and cognition. Specifically, I will determine whether kindling of different brain regions induces an aberrant form of hippocampal neurogenesis that contributes to cognitive dysfunction. In Chapter 5, I will investigate whether kindling of different brain regions alters different subpopulations of hippocampal GABAergic interneurons, in terms of number and morphological features. Finally, Chapter 6 will provide preliminary evidence that the cognitive impairments associated with kindling can be ameliorated through intrahippocampal infusions of recombinant reelin. The collection of studies in this dissertation improves our understanding of the relationship between aberrant plasticity and cognitive impairments associated with repeated convulsions

Desynchronization of Neocortical Networks by Asynchronous Release of GABA at Autaptic and Synaptic Contacts from Fast-Spiking Interneurons

An activity-dependent long-lasting asynchronous release of GABA from identified fast-spiking inhibitory neurons in the neocortex can impair the reliability and temporal precision of activity in a cortical network

Parvalbumin Interneurons of Hippocampus Tune Population Activity at Theta Frequency

SummaryHippocampal theta rhythm arises from a combination of recently described intrinsic theta oscillators and inputs from multiple brain areas. Interneurons expressing the markers parvalbumin (PV) and somatostatin (SOM) are leading candidates to participate in intrinsic rhythm generation and principal cell (PC) coordination in distal CA1 and subiculum. We tested their involvement by optogenetically activating and silencing PV or SOM interneurons in an intact hippocampus preparation that preserves intrinsic connections and oscillates spontaneously at theta frequencies. Despite evidence suggesting that SOM interneurons are crucial for theta, optogenetic manipulation of these interneurons modestly influenced theta rhythm. However, SOM interneurons were able to strongly modulate temporoammonic inputs. In contrast, activation of PV interneurons powerfully controlled PC network and rhythm generation optimally at 8 Hz, while continuously silencing them disrupted theta. Our results thus demonstrate a pivotal role of PV but not SOM interneurons for PC synchronization and the emergence of intrinsic hippocampal theta

Critical role of canonical transient receptor potential channel 7 in initiation of seizures

Status epilepticus (SE) is a life-threatening disease that has been recognized since antiquity but still causes over 50,000 deaths annually in the United States. The prevailing view on the pathophysiology of SE is that it is sustained by a loss of normal inhibitory mechanisms of neuronal activity. However, the early process leading to the initiation of SE is not well understood. Here, we show that, as seen in electroencephalograms, SE induced by the muscarinic agonist pilocarpine in mice is preceded by a specific increase in the gamma wave, and genetic ablation of canonical transient receptor potential channel (TRPC) 7 significantly reduces this pilocarpine-induced increase of gamma wave activity, preventing the occurrence of SE. At the cellular level, TRPC7 plays a critical role in the generation of spontaneous epileptiform burst firing in cornu ammonis (CA) 3 pyramidal neurons in brain slices. At the synaptic level, TRPC7 plays a significant role in the long-term potentiation at the CA3 recurrent collateral synapses and Schaffer collateral-CA1 synapses, but not at the mossy fiber-CA3 synapses. Taken together, our data suggest that epileptiform burst firing generated in the CA3 region by activity-dependent enhancement of recurrent collateral synapses may be an early event in the initiation process of SE and that TRPC7 plays a critical role in this cellular event. Our findings reveal that TRPC7 is intimately involved in the initiation of seizures both in vitro and in vivo. To our knowledge, this contribution to initiation of seizures is the first identified functional role for the TRPC7 ion channel.Fil: Phelan, K. D.. University of Arkansas for Medical Sciences; Estados UnidosFil: Shwe, U. T.. University of Arkansas for Medical Sciences; Estados UnidosFil: Abramowitz, J.. National Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences; Estados UnidosFil: Zheng, F.. University of Arkansas for Medical Sciences; Estados Unido

Aberrant structural and functional plasticity in the adult hippocampus of amygdala kindled rats

Amygdala kindling is commonly used to study the neural mechanisms of temporal lobe epilepsy and its behavioral consequences. The repetitive seizure activity that occurs during kindling is thought to induce an extensive array of structural and functional modifications within the brain, particularly in the hippocampus and dentate gyrus regions. Some of these changes include the growth or sprouting of new axonal connections as well as the birth and integration of new neurons into hippocampal circuits. Previous work has shown that these changes in structural and functional plasticity are not necessarily beneficial events. For instance, the growth and reorganization of synaptic terminals in the hippocampus and other brain regions might serve as a substrate that enhances hyperexcitability and seizure generation. In addition, although seizures induce the birth of new neurons, many of these newly generated cells migrate and function improperly within the hippocampal networks. Considering the prominent role of the hippocampus in a variety of behaviours, including learning, memory, and mood regulation, it would appear that alterations involving the structural and functional properties of both mature and newly born neurons in this region could impact these hippocampal-dependent functions. However, to date, the role of kindling-induced changes in hippocampal structural plasticity and neurogenesis on behaviour is incomplete, and the molecular mechanisms that govern these pathological events are poorly understood. The aim of this dissertation is to gain a better understanding of the changes in synaptic plasticity and neurogenesis within the hippocampus that occur after amygdala kindling. In chapter 2, we will examine if kindling alters the expression of synapsin I, a molecular marker of synaptic growth and activity, in both the hippocampus and other brain regions. In addition, we will also set out to determine if changes in synapsin I are related to the development of behavioural impairments associated with kindling. In chapter 3, the effect of kindling on hippocampal neurogenesis will be examined. In addition, we will also evaluate the effect of kindling on the expression of Reelin and Disrupted-in-Schizophrenia 1 (DISC1), two proteins instrumental for mediating proper neuronal migrational and maturation during development. In chapter 4, the effect of altered DISC1 expression in the dentate gyrus after kindling will be examined more extensively. We will examine whether altered DISC1 expression in the dentate contributes to some of the pathological features associated with seizure-induced hippocampal neurogenesis, such as ectopic cell migration and dentate granule cell layer dispersion. Finally, in chapter 5, the impact of aberrant seizure-induced neurogenesis on behaviour will be examined by determining if seizure-generated neurons functionally integrate and participate in hippocampal circuits related to memory processing. The results of this dissertation enhances our understanding of the functional consequences that altered hippocampal synaptic plasticity and neurogenesis may have on the development of epilepsy and emergence of cognitive impairments associated with chronic seizures

Novel roles of the endocannabinoid system in modulating synaptic plasticity

Learning and memory formation are invaluable processes in human life; however, the cellular mechanisms that control these phenomena are largely unknown. Synaptic plasticity, which is the ability of the synapse between two neurons to change in strength based on activity, is believed to be a key process in the formation of memories and learning. Endocannabinoids (eCB) have recently emerged as important modulators of synaptic plasticity but their precise roles and mechanisms are not well understood and many contradictions exist in the current literature. We have investigated the roles of eCBs and their primary receptor, the CB1 receptor, in the central nervous system using electrophysiological recordings in rodent hippocampus. We find that a moderate frequency 10 Hz stimulation protocol produces long-term potentiation (LTP) that is modulated by eCBs in both mice and rats; but surprisingly, the roles played by eCBs differ greatly between species. In rats, 10 Hz LTP requires CB1 receptor activation, as it is completely abolished by the CB1 antagonists AM251 and SR141716. Unlike theta burst stimulation (TBS) induced LTP, 10 Hz LTP does not require NMDA receptor activation. However, it is prevented when both NMDA and group1 mGluR receptors are blocked. The 10 Hz LTP is also independent of GABAergic synaptic inhibition, suggesting it is a novel form of excitatory synaptic plasticity mediated by the eCB system in hippocampus. In mice, we find that CB1 has an inhibitory effect on 10 Hz induced LTP. When the receptor is genetically removed in CB1 (-/-) mice or pharmacologically blocked wild type mice, 10 Hz LTP is greatly facilitated. Similar to TBS LTP, 10 Hz LTP in mice is NMDA receptor mediated. Also, the ability to achieve successful long-term depression (LTD) is decreased in CB1 (-/-) mice; yet, the magnitude of successful LTD is not changed. Together, this data supports a role for the CB1 receptor in inhibiting the induction of LTP with moderate stimulation protocols in mice, while in rats CB1 activation is required for 10 Hz LTP. Overall, our data supports that eCBs are crucial modulators of synaptic plasticity, although the roles they play may differ among species

A Selective Interplay between Aberrant EPSPKA and INaP Reduces Spike Timing Precision in Dentate Granule Cells of Epileptic Rats

Spike timing precision is a fundamental aspect of neuronal information processing in the brain. Here we examined the temporal precision of input–output operation of dentate granule cells (DGCs) in an animal model of temporal lobe epilepsy (TLE). In TLE, mossy fibers sprout and establish recurrent synapses on DGCs that generate aberrant slow kainate receptor–mediated excitatory postsynaptic potentials (EPSPKA) not observed in controls. We report that, in contrast to time-locked spikes generated by EPSPAMPA in control DGCs, aberrant EPSPKA are associated with long-lasting plateaus and jittered spikes during single-spike mode firing. This is mediated by a selective voltage-dependent amplification of EPSPKA through persistent sodium current (INaP) activation. In control DGCs, a current injection of a waveform mimicking the slow shape of EPSPKA activates INaP and generates jittered spikes. Conversely in epileptic rats, blockade of EPSPKA or INaP restores the temporal precision of EPSP–spike coupling. Importantly, EPSPKA not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through INaP activation. We conclude that a selective interplay between aberrant EPSPKA and INaP severely alters the temporal precision of EPSP–spike coupling in DGCs of chronic epileptic rats