Bridging the cleft at GABA synapses in the brain

Animals chronically administered with diazepam (DZM -2 mg/kg/day i.p.) or vehicle (VEH) for 21 days were tested in a fear-conditioning paradigm 4 days after the last administration. Increased freezing was observed in DZM withdrawn rats as compared to VEH injected control rats in both associative and nonassociative context and this increase was greatest for the DZM withdrawal group in the paired context. In animals anesthetized with urethane, single pulses in the medial prefrontal cortex evoked a field potential including a population spike (PS) in the basolateral complex of the amygdala (BLA) of control animals, whereas in DZM withdrawn animals multiple PSs were evoked. In brain slices from control rats, stimulation of the external capsule evoked a field potential including a PS in the BLA, whereas in DZM withdrawn rats multiple PSs were evoked. The amplitude of the PS was smaller in slices obtained from DZM withdrawn rats than from control rats, and paired pulse inhibition was significantly less in the former. Perfusion with DZM 2 mM of slices obtained from DZM withdrawn rats eliminated repetitive spiking. GABAergic blockade with 50 mM picrotoxin in control rats resulted in the appearance of multiple secondary PSs. In slices from DZM withdrawn rats high-frequency stimulation induced a highly significant potentiation that lasted at least 2 h (LTP), whereas in control rats the same stimulation did not induce LTP. Neuronal hyperexcitability leading to facilitated LTP observed in BLA of DZM withdrawn rats could be due to depressed GABAergic activity (dysinhibition). The increased synaptic plasticity may be at the root of the increased fear learning observed in withdrawn animals.

Section: Discussionsupporting

confidence: 82%

Increased Fear Learning Coincides with Neuronal Dysinhibition and Facilitated LTP in the Basolateral Amygdala following Benzodiazepine Withdrawal in Rats

Isoardi

Martijena

Carrer

et al. 2004

“…GlyT1 blockade increases the extracellular concentration of glycine (Martina et al, 2004), which not only facilitated NMDAR-mediated responses (Figure 4), but also activated GlyRs to induce tonic current ( Figure 5) and E-S depression (Figure 3) in hippocampal CA1 area. However, since no glycinergic neurotransmission has been found in the hippocampus (Mody et al, 1994), from where was this amino acid released?…”

Section: Is Glycine a Gliotransmitter?mentioning

confidence: 99%

“…Electrophysiological (Thio et al, 2003;Chattipakorn and McMahon, 2003), immunocytochemical (Becker et al, 1993), and in situ hybridization studies (Malosio et al, 1991) have shown that functional GlyRs are also present in many regions of developing and mature brain, including the hippocampus, where they are expressed by CA1 pyramidal cells and interneurons. Although no glycinergic synaptic transmission has been found in the hippocampus (Mody et al, 1994), accumulating evidence shows the presence of non-synaptic GlyRs containing at least a2 subunit (Chattipakorn and McMahon, 2002;Mori et al, 2002;Thio et al, 2003;Yoon et al, 1998). Thus, GlyRs are likely to have profound effects on cortical function, and may play a fundamental role in modulating hippocampal excitability.…”

Section: Introductionmentioning

confidence: 99%

Glycine Uptake Regulates Hippocampal Network Activity via Glycine Receptor-Mediated Tonic Inhibition

Zhang

Gong

et al. 2007

Functional glycine receptors (GlyRs) are enriched in the hippocampus, but their role in hippocampal function remains unclear. Since the concentration of ambient glycine is determined by the presence of powerful glycine transporter (GlyT), we blocked the reuptake of glycine in hippocampal slices to examine the role of GlyRs. Antagonists of GlyT type 1 (GlyT1) but not that of GlyT type 2 (GlyT2) induced excitatory postsynaptic potential (EPSP)-spike depression, which was reversed by the specific GlyR antagonist strychnine. Moreover, endogenously elevating the glycine concentration with the GlyT1 antagonists facilitated NMDA receptor-dependent longterm potentiation induction, and elicited a strychnine-sensitive chloride current. In addition, impairment of glial function with fluoroacetate blocked the effect of GlyT1 antagonists on the EPSP-spike curve. Furthermore, pretreatment with sarcosine was effective in controlling pentylenetetrazol-induced seizures. These results indicate an essential role of GlyTs in fine-tuning tonic activation of GlyRs and suggest a potential role of GlyR-dependent EPSP-spike depression in hippocampal network stability.

“…GABA (g-amino-butyric acid) is the primary inhibitory neurotransmitter in brain (Mody et al, 1994;Sieghart, 1995). Evidence accumulated over several decades suggested that ethanol influences GABA function (Allan and Harris, 1987;Frye and Breese, 1982;Liljequist and Engel, 1982;Martz et al, 1983;Mereu and Gessa, 1985;Nestoros, 1980;Simson et al, 1991;see Crews et al, 1996).…”

Section: Interaction Of Ethanol With the Gaba System In Vivomentioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.