Excitatory postsynaptic potentials in rat neocortical neurons in vitro. III. Effects of a quinoxalinedione non-NMDA receptor antagonist

1. Intracellular microelectrodes were used to obtain recordings from neurons in layer II/III of rat frontal cortex. A bipolar electrode positioned in layer IV of the neocortex was used to evoke postsynaptic potentials. Graded series of stimulation were employed to selectively activate different classes of postsynaptic responses. The sensitivity of postsynaptic potentials and iontophoretically applied neurotransmitters to the non-N-methyl-D-asparate (NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) was examined. 2. As reported previously, low-intensity electrical stimulation of cortical layer IV evoked short-latency early excitatory postsynaptic potentials (eEPSPs) in layer II/III neurons. CNQX reversibly antagonized eEPSPs in a dose-dependent manner. Stimulation at intensities just subthreshold for activation of inhibitory postsynaptic potentials (IPSPs) produced long-latency (10 to 40-ms) EPSPs (late EPSPs or 1EPSPs). CNQX was effective in blocking 1EPSPs. 3. With the use of stimulus intensities at or just below threshold for evoking an action potential, complex synaptic potentials consisting of EPSP-IPSP sequences were observed. Both early, Cl(-)-dependent and late, K(+)-dependent IPSPs were reduced by CNQX. This effect was reversible on washing. This disinhibition could lead to enhanced excitability in the presence of CNQX. 4. Iontophoretic application of quisqualate produced a membrane depolarization with superimposed action potentials, whereas NMDA depolarized the membrane potential and evoked bursts of action potentials. At concentrations up to 5 microM, CNQX selectively antagonized quisqualate responses. NMDA responses were reduced by 10 microM CNQX. D-Serine (0.5-2 mM), an agonist at the glycine regulatory site on the NMDA receptor, reversed the CNQX depression of NMDA responses

Preconditioning of low-frequency repetitive transcranial magnetic stimulation with transcranial direct current stimulation: evidence for homeostatic plasticity in the human motor cortex

Recent experimental work in animals has emphasized the importance of homeostatic plasticity as a means of stabilizing the properties of neuronal circuits. Here, we report a phenomenon that indicates a homeostatic pattern of cortical plasticity in healthy human subjects. The experiments combined two techniques that can produce long-term effects on the excitability of corticospinal output neurons: transcranial direct current stimulation (TDCS) and repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex. "Facilitatory preconditioning" with anodal TDCS caused a subsequent period of 1 Hz rTMS to reduce corticospinal excitability to below baseline levels for >20 min. Conversely, "inhibitory preconditioning" with cathodal TDCS resulted in 1 Hz rTMS increasing corticospinal excitability for at least 20 min. No changes in excitability occurred when 1 Hz rTMS was preceded by sham TDCS. Thus, changing the initial state of the motor cortex by a period of DC polarization reversed the conditioning effects of 1 Hz rTMS. These preconditioning effects of TDCS suggest the existence of a homeostatic mechanism in the human motor cortex that stabilizes corticospinal excitability within a physiologically useful range

Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

GABAB receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABAB receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABAB receptors. Here, we investigate the impact of GABAB receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABAB receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 μM), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABAB receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABAB receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABAB receptors regulated neuronal output in different ways. Activation of somatic GABAB receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABAB receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABAB receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABAB receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABAB receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.NHMR

Regulation of neuronal excitability through pumilio-dependent control of a sodium channel gene

Dynamic changes in synaptic connectivity and strength, which occur during both embryonic development and learning, have the tendency to destabilize neural circuits. To overcome this, neurons have developed a diversity of homeostatic mechanisms to maintain firing within physiologically defined limits. In this study, we show that activity-dependent control of mRNA for a specific voltage-gated Na+ channel [encoded by paralytic (para)] contributes to the regulation of membrane excitability in Drosophila motoneurons. Quantification of para mRNA, by real-time reverse-transcription PCR, shows that levels are significantly decreased in CNSs in which synaptic excitation is elevated, whereas, conversely, they are significantly increased when synaptic vesicle release is blocked. Quantification of mRNA encoding the translational repressor pumilio (pum) reveals a reciprocal regulation to that seen for para. Pumilio is sufficient to influence para mRNA. Thus, para mRNA is significantly elevated in a loss-of-function allele of pum (pumbemused), whereas expression of a full-length pum transgene is sufficient to reduce para mRNA. In the absence of pum, increased synaptic excitation fails to reduce para mRNA, showing that Pum is also necessary for activity-dependent regulation of para mRNA. Analysis of voltage-gated Na+ current (INa) mediated by para in two identified motoneurons (termed aCC and RP2) reveals that removal of pum is sufficient to increase one of two separable INa components (persistent INa), whereas overexpression of a pum transgene is sufficient to suppress both components (transient and persistent). We show, through use of anemone toxin (ATX II), that alteration in persistent INa is sufficient to regulate membrane excitability in these two motoneurons

Experience-driven formation of parts-based representations in a model of layered visual memory

Growing neuropsychological and neurophysiological evidence suggests that the visual cortex uses parts-based representations to encode, store and retrieve relevant objects. In such a scheme, objects are represented as a set of spatially distributed local features, or parts, arranged in stereotypical fashion. To encode the local appearance and to represent the relations between the constituent parts, there has to be an appropriate memory structure formed by previous experience with visual objects. Here, we propose a model how a hierarchical memory structure supporting efficient storage and rapid recall of parts-based representations can be established by an experience-driven process of self-organization. The process is based on the collaboration of slow bidirectional synaptic plasticity and homeostatic unit activity regulation, both running at the top of fast activity dynamics with winner-take-all character modulated by an oscillatory rhythm. These neural mechanisms lay down the basis for cooperation and competition between the distributed units and their synaptic connections. Choosing human face recognition as a test task, we show that, under the condition of open-ended, unsupervised incremental learning, the system is able to form memory traces for individual faces in a parts-based fashion. On a lower memory layer the synaptic structure is developed to represent local facial features and their interrelations, while the identities of different persons are captured explicitly on a higher layer. An additional property of the resulting representations is the sparseness of both the activity during the recall and the synaptic patterns comprising the memory traces.Comment: 34 pages, 12 Figures, 1 Table, published in Frontiers in Computational Neuroscience (Special Issue on Complex Systems Science and Brain Dynamics), http://www.frontiersin.org/neuroscience/computationalneuroscience/paper/10.3389/neuro.10/015.2009

Logarithmic distributions prove that intrinsic learning is Hebbian

In this paper, we present data for the lognormal distributions of spike rates, synaptic weights and intrinsic excitability (gain) for neurons in various brain areas, such as auditory or visual cortex, hippocampus, cerebellum, striatum, midbrain nuclei. We find a remarkable consistency of heavy-tailed, specifically lognormal, distributions for rates, weights and gains in all brain areas examined. The difference between strongly recurrent and feed-forward connectivity (cortex vs. striatum and cerebellum), neurotransmitter (GABA (striatum) or glutamate (cortex)) or the level of activation (low in cortex, high in Purkinje cells and midbrain nuclei) turns out to be irrelevant for this feature. Logarithmic scale distribution of weights and gains appears to be a general, functional property in all cases analyzed. We then created a generic neural model to investigate adaptive learning rules that create and maintain lognormal distributions. We conclusively demonstrate that not only weights, but also intrinsic gains, need to have strong Hebbian learning in order to produce and maintain the experimentally attested distributions. This provides a solution to the long-standing question about the type of plasticity exhibited by intrinsic excitability

Dopaminergic Regulation of Neuronal Circuits in Prefrontal Cortex

Neuromodulators, like dopamine, have considerable influence on the\ud processing capabilities of neural networks. \ud This has for instance been shown in the working memory functions\ud of prefrontal cortex, which may be regulated by altering the\ud dopamine level. Experimental work provides evidence on the biochemical\ud and electrophysiological actions of dopamine receptors, but there are few \ud theories concerning their significance for computational properties \ud (ServanPrintzCohen90,Hasselmo94).\ud We point to experimental data on neuromodulatory regulation of \ud temporal properties of excitatory neurons and depolarization of inhibitory \ud neurons, and suggest computational models employing these effects.\ud Changes in membrane potential may be modelled by the firing threshold,\ud and temporal properties by a parameterization of neuronal responsiveness \ud according to the preceding spike interval.\ud We apply these concepts to two examples using spiking neural networks.\ud In the first case, there is a change in the input synchronization of\ud neuronal groups, which leads to\ud changes in the formation of synchronized neuronal ensembles.\ud In the second case, the threshold\ud of interneurons influences lateral inhibition, and the switch from a \ud winner-take-all network to a parallel feedforward mode of processing.\ud Both concepts are interesting for the modeling of cognitive functions and may\ud have explanatory power for behavioral changes associated with dopamine \ud regulation

PTEN: A master regulator of neuronal structure, function, and plasticity.

PTEN (phosphatase and tensin homolog on chromosome ten) is a dual protein/lipid phosphatase that dephosphorylates PIP3, thereby inhibiting the AKT/mTOR pathway. This inhibition ultimately decreases protein translation, cell proliferation and cell growth. In the central nervous system, inhibition of PTEN leads to increased stem cell proliferation, somatic, dendritic and axonal growth, accelerated spine maturation, diminished synaptic plasticity, and altered intrinsic excitability. In agreement with these findings, patients carrying single-copy inactivating mutations of PTEN suffer from autism, macrocephaly, mental retardation, and epilepsy.(1) (-) (9) Understanding the mechanisms through which PTEN modulates the structure, function, and plasticity of cortical networks is a major focus of study. Preventing and reversing the changes induced by loss of Pten in model animals will pave the way for treatments in humans