[Show abstract][Hide abstract] ABSTRACT: Endocannabinoids are lipid derivatives that mediate paracrine and juxtacrine signaling between cells. In the hippocampal CA1 region, a retrograde endocannabinoid signal suppresses GABA release by acting on presynaptic cannabinoid receptor-1 (CB1) and can be functionally manifested as depolarization-induced suppression of inhibition (DSI). In the present study, whole cell patch-clamp recordings in hippocampal slices were made to examine DSI in rats from P7-P21. Robust DSI develops in rat hippocampus at postnatal ages greater than two weeks, but only modest DSI is observed in P7-9 rat. DSI in neonatal rats can be enhanced by activation of group I metabotropic glutamate receptors (mGluRs) or muscarinic acetylcholine receptors in those neonatal rats. The DSI is also enhanced by sustained low-frequency (1 Hz) stimulation (5 min). This stimulus-enhanced DSI was prevented in the presence of 6-methyl-2-(phenylethynyl)-pyridine (10 microM), a group I mGluR antagonist. WIN55212-2, a synthetic CB1 agonist, produced a similar level of inhibition of GABAergic synaptic transmission at different postnatal time points. Therefore postsynaptic mechanisms appear to be mainly responsible for developmental changes in DSI, although presynaptic mechanisms cannot be ruled out entirely. We have also obtained evidence that tonic endocannabinoid release suppresses GABAergic transmission in the mature but not the neonatal hippocampus. The differential DSI magnitude at different stages of maturation could alter synaptic plasticity and learning and memory during hippocampal development.
Journal of Neurophysiology 12/2009; 103(2):1123-9. DOI:10.1152/jn.00327.2009 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Learning and memory are thought to involve activity-dependent changes in synaptic efficacy such as long-term potentiation (LTP) and long-term depression (LTD). Recent studies have indicated that endocannabinoid-dependent modulation of inhibitory transmission facilitates induction of hippocampal LTP and that endocannabinoids play a key role in certain forms of LTD. Here, we show that repetitive low-frequency synaptic stimulation (LFS) produces persistent up-regulation of endocannabinoid signaling at hippocampal CA1 GABAergic synapses. This LFS also produces LTD of inhibitory synapses and facilitates LTP at excitatory, glutamatergic synapses. These endocannabinoid-mediated plastic changes could contribute to information storage within the brain.
Journal of Neurophysiology 06/2007; 97(6):4386-9. DOI:10.1152/jn.01228.2006 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interactions between ethanol and synaptic transmission mediated by gamma -amino-N-butyric acid (GABA) have been suggested to contribute to alcohol intoxication. Ethanol effects on postsynaptic GABAA receptors have been the major focus of this line of research. There is increasing evidence that ethanol potentiation of GABAergic transmission involves increased GABA release from presynaptic terminals. In the present study, a mechanically isolated neuron/bouton preparation from the basolateral amygdala was used to examine the effects of ethanol on spontaneous GABAergic synaptic currents elicited by GABA release from the presynaptic terminals. We found that ethanol application produced a rapid increase in the frequency of spontaneous GABAergic synaptic currents. An acute tolerance to ethanol was also observed, and this tolerance involved GABAB receptor activation. The ethanol-induced potentiation did not involve alterations in the function of postsynaptic GABAA receptors and was independent of presynaptic action potential firing. These findings indicate that ethanol potentiates GABA release, most likely via a direct action on presynaptic boutons.
Journal of Neurophysiology 08/2006; 96(1):433-41. DOI:10.1152/jn.01380.2005 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This article presents the proceedings of a symposium entitled "The Tipsy Terminal: Presynaptic Effects of Ethanol" (held at the annual meeting of the Research Society on Alcoholism, in Santa Barbara, CA, June 27, 2005). The objective of this symposium was to focus on a cellular site of ethanol action underrepresented in the alcohol literature, but quickly becoming a "hot" topic. The chairs of the session were Marisa Roberto and George Robert Siggins. Our speakers were chosen on the basis of the diverse electrophysiological and other methods used to discern the effects of acute and chronic ethanol on presynaptic terminals and on the basis of significant insights that their data provide for understanding ethanol actions on neurons in general, as mechanisms underlying problematic behavioral effects of alcohol. The 5 presenters drew from their recent studies examining the effects of acute and chronic ethanol using a range of sophisticated methods from electrophysiological analysis of paired-pulse facilitation and spontaneous and miniature synaptic currents (Drs. Weiner, Valenzuela, Zhu, and Morrisett), to direct recording of ion channel activity and peptide release from acutely isolated synaptic terminals (Dr. Treistman), to direct microscopic observation of vesicular release (Dr. Morrisett). They showed that ethanol administration could both increase and decrease the probability of release of different transmitters from synaptic terminals. The effects of ethanol on synaptic terminals could often be correlated with important behavioral or developmental actions of alcohol. These and other novel findings suggest that future analyses of synaptic effects of ethanol should attempt to ascertain, in multiple brain regions, the role of presynaptic terminals, relevant presynaptic receptors and signal transduction linkages, exocytotic mechanisms, and their involvement in alcohol's behavioral actions. Such studies could lead to new treatment strategies for alcohol intoxication, alcohol abuse, and alcoholism.
Alcoholism Clinical and Experimental Research 03/2006; 30(2):222-32. DOI:10.1111/j.1530-0277.2006.00030.x · 3.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Repetitive firing neuron or activation of synaptic transmission plays an important role in the modulation of synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). These activity-dependent changes in synaptic efficacy are thought to be critical to learning and memory; however, the underlying mechanisms remain to be defined. Endogenous cannabinoids (eCBs) are diffusible modulators that are released from depolarized postsynaptic neurons and act on presynaptic terminals. Persistent release of eCBs can lead to long-term modulation of synaptic plasticity in the brain. Given a broad distribution of eCB receptors in the brain, the eCB signaling system could contribute to use-dependent modification of brain functions.
Critical Reviews in Neurobiology 02/2006; 18(1-2):113-24. DOI:10.1615/CritRevNeurobiol.v18.i1-2.120
[Show abstract][Hide abstract] ABSTRACT: The basolateral amygdala (BLA) is a critical component of the amygdaloid circuit, which is thought to be involved in fear conditioned responses. Using whole cell patch-clamp recording, we found that activation of nicotinic acetylcholine receptors (nAChRs) leads to an action potential-dependent increase in the frequency of spontaneous GABAergic currents in principal neurons in the BLA. These spontaneous GABAergic currents were abolished by a low-Ca2+/high-Mg2+ bathing solution, suggesting that they are spontaneous inhibitory postsynaptic currents (sIPSCs). Blockade of ionotropic glutamate receptors did not prevent this increased frequency of sIPSCs nor did blockade of alpha7 nAChRs. Among the nAChR agonists tested, cystisine was more effective at increasing the frequency of the sIPSCs than nicotine or 1,1-dimethyl-4-phenyl piperazinium iodide, consistent with a major contribution of beta4 nAChR subunits. The nicotinic antagonist, dihydro-beta-erythroidine, was less effective than d-tubocurarine in blocking the increased sIPSC frequency induced by ACh, suggesting that alpha4-containing nAChR subunits do not play a major role in the ACh-induced increased sIPSC frequency. Although alpha2/3/4/7 and beta2/4 nAChR subunits were found in the BLA by RT-PCR, the agonist and antagonist profiles suggest that the ACh-induced increase in sIPSC frequency involves predominantly alpha3beta4-containing nAChR subunits. Consistent with this, alpha-conotoxin-AuIB, a nAChR antagonist selective for the alpha3beta4 subunit combination, inhibited the ACh-induced increase in the frequency of sIPSCs. The observations suggest that nicotinic activation increases the frequency of sIPSCs in the BLA by acting mainly on alpha3beta4-containing nicotinic receptors on GABAergic neurons and may play an important role in the modulation of synaptic transmission in the amygdala.
Journal of Neurophysiology 12/2005; 94(5):3081-91. DOI:10.1152/jn.00974.2004 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retrograde synaptic signaling by endogenous cannabinoids (endocannabinoids) is a recently discovered form of neuromodulation in the brain. In the basolateral amygdala (BLA), endocannabinoid signaling has been implicated in learning and memory, specifically in extinction of aversive memories. To examine retrograde endocannabinoid signaling in this brain region, BLA neurons were freshly isolated using an enzyme-free procedure. These isolated neurons retain attached functional excitatory and inhibitory synaptic boutons. Spontaneous GABAergic IPSCs (sIPSCs) were isolated from these freshly isolated neurons and a 4 s step of depolarization from -60 to 0 mV produced suppression of sIPSC frequency and amplitude. A similar depolarization-induced suppression of inhibition (DSI) was observed in neurons in BLA slices. DSI in the single-cell preparation was abolished by the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, and DSI duration was shortened in the presence of 2-methyl-6-(phenylethynyl) pyridine, an mGluR5 (metabotropic glutamate receptor 5) antagonist. The initial decrease in sIPSCs induced by the DSI procedure was greatly attenuated in recordings with 20 mm BAPTA containing postsynaptic internal solution, but a delayed-onset decrease was observed under this recording condition. A CB1 agonist decreased sIPSC frequency and amplitude, whereas CB1 antagonists increased these responses. The antagonist-induced increase was abolished in 20 mm BAPTA-filled cells. These data provide solid evidence for retrograde endocannabinoid signaling in the BLA and also indicate that this retrograde signaling requires only a postsynaptic neuron and attached synaptic boutons.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2005; 25(26):6199-207. DOI:10.1523/JNEUROSCI.1148-05.2005 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dynorphin A (DynA), an endogenous agonist of kappa-opioid receptors, has also been reported to directly interact with the NMDA receptor. DynA inhibition of NMDA receptor function has been suggested to be involved in its neuroprotective action during ischemic and acidic conditions. However, the effect of external pH on DynA inhibition of the NMDA receptor has not been reported. Here, we show that DynA inhibition of the NMDA receptor is dependent on extracellular pH over the range of pH 6.7-8.3, and the inhibition by 10 microM DynA increases at low pH by three- to four-fold in hippocampal neurons and in Xenopus oocytes expressing NR1-1a/2B subunits. Molecular studies showed that the interacting site for DynA on the NMDA receptor is distinct from that of proton or redox sites. Peptide mapping demonstrated important contributions of positively charged residues and specific structural organization of the peptide to the potency of DynA inhibition. Thus, DynA inhibits NMDA receptors through an allosteric mechanism, which is pH dependent and involves the specific structural features of the peptide.