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ABSTRACT: The lateral hypothalamus and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake, while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at serine 845 (pSer(845)) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through G(i/o), and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSCs) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K(+) channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake.
Journal of Neuroscience 06/2010; 30(24):8263-73. · 7.11 Impact Factor
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ABSTRACT: Recent studies have demonstrated that GABAergic synaptic transmission among neostriatal spiny projection neurons (SPNs) is strongly modulated by dopamine with individual connections exhibiting either D(1) receptor (D(1)R)-mediated facilitation or D(2) receptor (D(2)R)-mediated inhibition and, at least in some preparations, a subset of connections exhibiting both of these effects. In light of the cell type-specific expression of D(1a)R in striatonigral and D(2)R in striatopallidal neurons and the differential expression of the other D(1) and D(2) family dopamine receptors, we hypothesize that the nature of the dopaminergic modulation is specific to the types of SPNs that participate in the connection. Here the biophysical properties and dopaminergic modulation of intrastriatal connections formed by striatopallidal neurons were examined. Contrary to previous expectation, synapses formed by striatopallidal neurons were biophysically and pharmacologically heterogeneous. Two distinct types of axon collateral connections could be distinguished among striatopallidal neurons. The more common, small-amplitude connections (80%) exhibited mean IPSC amplitudes several times smaller than their less frequent large-amplitude counterparts, principally because of a smaller number of release sites involved. The two types of connections were also differentially regulated by dopamine. Small-amplitude connections exhibited strong and exclusively D(2)R-mediated presynaptic inhibition, whereas large-amplitude connections were unresponsive to dopamine. Synaptic connections from striatopallidal to striatonigral neurons exhibited exclusively D(2)R-mediated presynaptic inhibition that was similar to the regulation of small-amplitude connections between pairs of striatopallidal cells. Together, these findings demonstrate a previously unrecognized complexity in the organization and dopaminergic control of synaptic communication among SPNs.
Journal of Neuroscience 08/2009; 29(28):8977-90. · 7.11 Impact Factor
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ABSTRACT: We studied inositol-1,4,5-trisphosphate (IP(3)) receptor-dependent intracellular Ca(2+) waves in CA1 hippocampal and layer V medial prefrontal cortical pyramidal neurons using whole-cell patch-clamp recordings and Ca(2+) fluorescence imaging. We observed that Ca(2+) waves propagate in a saltatory manner through dendritic regions where increases in the intracellular concentration of Ca(2+) ([Ca(2+)](i)) were large and fast ('hot spots') separated by regions where increases in [Ca(2+)](i) were comparatively small and slow ('cold spots'). We also observed that Ca(2+) waves typically initiate in hot spots and terminate in cold spots, and that most hot spots, but few cold spots, are located at dendritic branch points. Using immunohistochemistry, we found that IP(3) receptors (IP(3)Rs) are distributed in clusters along pyramidal neuron dendrites and that the distribution of inter-cluster distances is nearly identical to the distribution of inter-hot spot distances. These findings support the hypothesis that the dendritic locations of Ca(2+) wave hot spots in general, and branch points in particular, are specially equipped for regenerative IP(3)R-dependent internal Ca(2+) release. Functionally, the observation that IP(3)R-dependent [Ca(2+)](i) rises are greater at branch points raises the possibility that this novel Ca(2+) signal may be important for the regulation of Ca(2+)-dependent processes in these locations. Futhermore, the observation that Ca(2+) waves tend to fail between hot spots raises the possibility that influences on Ca(2+) wave propagation may determine the degree of functional association between distinct Ca(2+)-sensitive dendritic domains.
The Journal of Physiology 03/2009; 587(Pt 7):1439-59. · 4.72 Impact Factor
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ABSTRACT: Calcium ions (Ca(2+)) released from inositol trisphosphate (IP(3))-sensitive intracellular stores may participate in both the transient and extended regulation of neuronal excitability in neocortical and hippocampal pyramidal neurons. IP(3) receptor (IP(3)R) antagonists represent an important tool for dissociating these consequences of IP(3) generation and IP(3)R-dependent internal Ca(2+) release from the effects of other, concurrently stimulated second messenger signaling cascades and Ca(2+) sources. In this study, we have described the actions of the IP(3)R and store-operated Ca(2+) channel antagonist, 2-aminoethoxydiphenyl-borate (2-APB), on internal Ca(2+) release and plasma membrane excitability in neocortical and hippocampal pyramidal neurons. Specifically, we found that a dose of 2-APB (100 microM) sufficient for attenuating or blocking IP(3)-mediated internal Ca(2+) release also raised pyramidal neuron excitability. The 2-APB-dependent increase in excitability reversed upon washout and was characterized by an increase in input resistance, a decrease in the delay to action potential onset, an increase in the width of action potentials, a decrease in the magnitude of afterhyperpolarizations (AHPs), and an increase in the magnitude of post-spike afterdepolarizations (ADPs). From these observations, we conclude that 2-APB potently and reversibly increases neuronal excitability, likely via the inhibition of voltage- and Ca(2+)-dependent potassium (K(+)) conductances.
Cell calcium 01/2009; 45(3):310-7. · 4.29 Impact Factor
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ABSTRACT: Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP3-PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP3 receptor (IP3R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP3R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP3R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.
Learning & memory (Cold Spring Harbor, N.Y.) 04/2008; 15(3):93-6. · 4.08 Impact Factor
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ABSTRACT: Factors that influence the activity of prefrontal cortex (PFC) pyramidal neurons are likely to play an important role in working memory function. One such factor may be the release of Ca2+ from intracellular stores. Here we investigate the hypothesis that metabotropic glutamate receptors (mGluRs)-mediated waves of internally released Ca2+ can regulate the intrinsic excitability and firing patterns of PFC pyramidal neurons. Synaptic or focal pharmacological activation of mGluRs triggered Ca2+ waves in the dendrites and somata of layer V medial PFC pyramidal neurons. These Ca2+ waves often evoked a transient SK-mediated hyperpolarization followed by a prolonged depolarization that respectively decreased and increased neuronal excitability. Generation of the hyperpolarization depended on whether the Ca2+ wave invaded or came near to the soma. The depolarization also depended on the extent of Ca2+ wave propagation. We tested factors that influence the propagation of Ca2+ waves into the soma. Stimulating more synapses, increasing inositol trisphosphate concentration near the soma, and priming with physiological trains of action potentials all enhanced the amplitude and likelihood of evoking somatic Ca2+ waves. These results suggest that mGluR-mediated Ca2+ waves may regulate firing patterns of PFC pyramidal neurons engaged by working memory, particularly under conditions that favor the propagation of Ca2+ waves into the soma.
Cerebral Cortex 03/2008; 18(2):407-23. · 6.54 Impact Factor
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ABSTRACT: Ca2+ waves provide a spatially and temporally unique intracellular signal that carries information from one region of the neuron
to another. Despite the computational potential of such a mechanism, relatively little is known about the consequences of
Ca2+ waves on neuronal function. In this chapter we review the basic properties of internal Ca2+ release and Ca2+ waves in hippocampal CA1 pyramidal neurons and how synaptically elicited Ca2+ waves influence the transcription factor CREB in an age-dependent manner.
12/2007: pages 73-89;
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ABSTRACT: The mammalian hippocampus, together with subcortical and cortical areas, is responsible for some forms of learning and memory. Proper hippocampal function depends on the highly dynamic nature of its circuitry, including the ability of synapses to change their strength for brief to long periods of time. In this study, we focused on a transient depression of glutamatergic synaptic transmission at Schaffer collateral synapses in acute hippocampal slices. The depression of evoked excitatory postsynaptic current (EPSC) amplitudes, herein called transient depression, follows brief trains of synaptic stimulation in stratum radiatum of CA1 and lasts for 2-3 min. Depression results from a decrease in presynaptic glutamate release, as NMDA-receptor-mediated EPSCs and composite EPSCs are depressed similarly and depression is accompanied by an increase in the paired-pulse ratio. Transient depression is prevented by blockade of metabotropic glutamate and acetylcholine receptors, presumably located presynaptically. These two receptor types--acting together--cause depression. Blockade of a single receptor type necessitates significantly stronger conditioning trains for triggering depression. Addition of an acetylcholinesterase inhibitor enables depression from previously insufficient conditioning trains. Furthermore, a strong coincident, but not causal, relationship existed between presynaptic depression and postsynaptic internal Ca(2+) release, emphasizing the potential importance of functional interactions between presynaptic and postsynaptic effects of convergent cholinergic and glutamatergic inputs to CA1. These convergent afferents, one intrinsic to the hippocampus and the other likely originating in the medial septum, may regulate CA1 network activity, the induction of long-term synaptic plasticity, and ultimately hippocampal function.
Journal of Neurophysiology 07/2007; 97(6):4108-19. · 3.32 Impact Factor
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ABSTRACT: Ca2+ signals in neurons use specific temporal and spatial patterns to encode unambiguous information about crucial cellular functions. To understand the molecular basis for initiation and propagation of inositol 1,4,5-trisphosphate (InsP3)-mediated intracellular Ca2+ signals, we correlated the subcellular distribution of components of the InsP3 pathway with measurements of agonist-induced intracellular Ca2+ transients in cultured rat hippocampal neurons and pheochromocytoma cells. We found specialized domains with high levels of phosphatidylinositol-4-phosphate kinase (PIPKI) and chromogranin B (CGB), proteins acting synergistically to increase InsP3 receptor (InsP3R) activity and sensitivity. In contrast, Ca2+ pumps in the plasma membrane (PMCA) and sarco-endoplasmic reticulum as well as buffers that antagonize the rise in intracellular Ca2+ were distributed uniformly. By pharmacologically blocking phosphatidylinositol-4-kinase and PIPKI or disrupting the CGB-InsP3R interaction by transfecting an interfering polypeptide fragment, we produced major changes in the initiation site and kinetics of the Ca2+ signal. This study shows that a limited number of proteins can reassemble to form unique, spatially restricted signaling domains to generate distinctive signals in different regions of the same neuron. The finding that the subcellular location of initiation sites and protein microdomains was cell type specific will help to establish differences in spatiotemporal Ca2+ signaling in different types of neurons.
Journal of Neuroscience 04/2005; 25(11):2853-64. · 7.11 Impact Factor
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ABSTRACT: The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+ ([Ca2+]i). Ca2+ is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+ compounds to test whether a postsynaptic rise in [Ca2+]i is sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]i to approximately 1 microm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+ buffer capacity than CA1 neurons, limiting the rise in [Ca2+]i achievable by photolysis. This [Ca2+]i rise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.
Journal of Neurophysiology 05/2004; 91(4):1596-607. · 3.32 Impact Factor
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Kazu Nakazawa,
Michael C Quirk,
Raymond A Chitwood,
Masahiko Watanabe, Mark F Yeckel,
Linus D Sun,
Akira Kato,
Candice A Carr,
Daniel Johnston,
Matthew A Wilson,
Susumu Tonegawa
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ABSTRACT: Pattern completion, the ability to retrieve complete memories on the basis of incomplete sets of cues, is a crucial function of biological memory systems. The extensive recurrent connectivity of the CA3 area of hippocampus has led to suggestions that it might provide this function. We have tested this hypothesis by generating and analyzing a genetically engineered mouse strain in which the N-methyl-D-asparate (NMDA) receptor gene is ablated specifically in the CA3 pyramidal cells of adult mice. The mutant mice normally acquired and retrieved spatial reference memory in the Morris water maze, but they were impaired in retrieving this memory when presented with a fraction of the original cues. Similarly, hippocampal CA1 pyramidal cells in mutant mice displayed normal place-related activity in a full-cue environment but showed a reduction in activity upon partial cue removal. These results provide direct evidence for CA3 NMDA receptor involvement in associative memory recall.
Science 08/2002; 297(5579):211-8. · 31.20 Impact Factor
