Potentiation of Glutamatergic Synaptic Transmission Onto Dorsal Raphe Serotonergic Neurons in the Valproic Acid Model of Autism

Autism spectrum disorder (ASD) is characterized by social and communicative impairments and increased repetitive behaviors. These symptoms are often comorbid with increased anxiety. Prenatal exposure to valproic acid (VPA), an anti-seizure and mood stabilizer medication, is a major environmental risk factor of ASD. Given the important role of the serotonergic (5-HT) system in anxiety, we examined the impact of prenatal VPA exposure on the function of dorsal raphe nucleus (DRn) 5-HT neurons. We found that male rats prenatally exposed to VPA exhibited increased anxiety-like behaviors revealed by a decreased time spent on the open arms of the elevated plus maze. Prenatal VPA exposed rats also exhibited a stereotypic behavior as indicated by excessive self-grooming in a novel environment. These behavioral phenotypes were associated with increased electrical activity of putative DRn 5-HT neurons recorded in vitro. Examination of underlying mechanisms revealed that prenatal VPA exposure increased excitation/inhibition ratio in synapses onto these neurons. The effect was mainly mediated by enhanced glutamate but not GABA release. We found reduced paired-pulse ratio (PPR) of evoked excitatory postsynaptic currents (EPSCs) and increased frequency but not amplitude of miniature EPSCs in VPA exposed rats. On the other hand, presynaptic GABA release did not change in VPA exposed rats, as the PPR of evoked inhibitory postsynaptic currents was unaltered. Furthermore, the spike-timing-dependent long-term potentiation at the glutamatergic synapses was occluded, indicating glutamatergic synaptic transmission is maximized. Lastly, VPA exposure did not alter the intrinsic membrane properties of DRn 5-HT neurons. Taken together, these results indicate that prenatal VPA exposure profoundly enhances glutamatergic synaptic transmission in the DRn and increases spontaneous firing in DRn 5-HT neurons, which could lead to increased serotonergic tone and underlie the increased anxiety and stereotypy after prenatal VPA exposure

Endocannabinoids Suppress Excitatory Synaptic Transmission to Dorsal Raphe Serotonin Neurons through the Activation of Presynaptic CB1 Receptors

Endocannabinoid signaling in the dorsal raphe (DR) has recently been implicated in the regulation of anxiety and depression. However, the cellular mechanisms by which endocannabinoids (eCBs) regulate the excitability of DR 5-hydroxytryptamine (serotonin; 5-HT) neurons remain poorly understood. In the present study, using whole-cell recording from DR 5-HT neurons, we examined the effects of eCBs on glutamatergic synapses in the DR. We found that the eCB anandamide decreased the amplitude of evoked excitatory postsynaptic currents (eEPSCs). This effect was blocked by CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251) and mimicked by (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2), a CB1 receptor agonist. The inhibition of eEPSC amplitude was associated with an increase in the paired-pulse ratio and coefficient of variance. Activation of CB1 receptors also reduced the frequency, but not the amplitude, of miniature excitatory postsynaptic currents, indicating that eCBs inhibit glutamate release in the DR. In addition, we found that depolarization of DR 5-HT neurons induced a transient inhibition of the amplitude of eEPSCs, termed depolarization-induced suppression of excitation (DSE). The induction of DSE required an increase in postsynaptic intracellular calcium and was due to a decrease in glutamate release. Furthermore, pharmacological studies showed that blockade of CB1 receptors with AM 251 abolished the DSE. In contrast, activation of CB1 receptors with WIN 55,212-2 mimicked and occluded the DSE, indicating that depolarization of DR 5-HT neurons triggers eCB release, which in turn mediates the DSE. Together, these results indicate that eCBs play a role in modulating glutamatergic synaptic transmission to DR 5-HT neurons

Oxytocin excites dorsal raphe serotonin neurons and bidirectionally gates their glutamate synapses

Summary: Oxytocin (OXT) modulates wide spectrum of social and emotional behaviors via modulation of numerous neurotransmitter systems, including serotonin (5-HT). However, how OXT controls the function of dorsal raphe nucleus (DRN) 5-HT neurons remains unknown. Here, we reveal that OXT excites and alters the firing pattern of 5-HT neurons via activation of postsynaptic OXT receptors (OXTRs). In addition, OXT induces cell-type-specific depression and potentiation of DRN glutamate synapses by two retrograde lipid messengers, 2-arachidonoylglycerol (2-AG) and arachidonic acid (AA), respectively. Neuronal mapping demonstrates that OXT preferentially potentiates glutamate synapses of 5-HT neurons projecting to medial prefrontal cortex (mPFC) and depresses glutamatergic inputs to 5-HT neurons projecting to lateral habenula (LHb) and central amygdala (CeA). Thus, by engaging distinct retrograde lipid messengers, OXT exerts a target-specific gating of glutamate synapses on the DRN. As such, our data uncovers the neuronal mechanisms by which OXT modulates the function of DRN 5-HT neurons

Effects of prenatal ethanol exposure on the excitability of ventral tegmental area dopamine neurons in vitro. J Pharmacol Exp Ther (2006

ABSTRACT Prenatal ethanol exposure leads to a persistent reduction in the number of spontaneously active dopaminergic (DA) neurons (DA neuron population activity) in the ventral tegmental area (VTA) in developing and adult animals. This effect might contribute to the dysfunction of the mesolimbic/cortical DA system and attention problems in children with fetal alcohol spectrum disorders. To characterize the underlying cellular mechanism for prenatal ethanol exposure-induced reduction in VTA DA neuron population activity, we used the whole-cell patch-clamp technique to study the membrane properties of putative VTA DA neurons in brain slices in 2-to 3-week-old control and prenatal ethanol-exposed animals. The results show that prenatal ethanol exposure did not impair the spontaneous pacemaker activity in putative VTA DA neurons but reduced the frequency of evoked action potentials. In addition, prenatal ethanol exposure led to a reduction in hyperpolarization-induced cation current (I h ) and an up-regulation of somatodendritic DA autoreceptors. The above prenatal ethanol exposureinduced changes could decrease the excitability of VTA DA neurons. However, they do not seem to play a role in reduced VTA DA neuron population activity in vivo, an effect thought to be mediated by excessive excitation leading to depolarization inactivation. Taken together, the above results indicate that prenatal ethanol exposure-induced reduction in VTA DA neuron population activity in vivo is not caused by changes in the intrinsic pacemaker activity or other membrane properties and could instead be caused by altered inputs to VTA DA neurons. Attention problems observed in children are among the most prominent behavioral abnormalities of fetal alcohol spectrum disorders (FASDs) The prenatal ethanol exposure-induced dysfunctions in the mesolimbic/cortical DA system include reduced DA synthesis, uptake sites, receptor binding sites, and DA metabolites in both DA neuron cell body and terminal area

Serotonin Neurons through the Activation of Nonselective Cationic Conductance

The dorsal raphe (DR) receives a prominent dopamine (DA) input that has been suggested to play a key role in the regulation of central serotoninergic transmission. DA is known to directly depolarize DR serotonin neurons, but the underlying mechanisms are not well understood. Here, we show that activation of D 2-like dopamine receptors on DR 5-HT neurons elicits a membrane depolarization and an inward current associated with an increase in membrane conductance. The DAinduced inward current (I DA) exhibits a linear I-V relationship and reverses polarity at around �15 mV, suggesting the involvement of a mixed cationic conductance. Consistent with this notion, lowering the extracellular concentration of sodium reduces the amplitude of I DA and induces a negative shift of its reversal potential to approximately �45 mV. This current is abolished by inhibiting G-protein function with GDP�S. Exam-The dorsal raphe (DR) nucleus, a major source of serotonin (5-HT) in the mammalian brain, plays an important role in the regulation of many physiological processes such as sleep/ arousal, food intake and mood (Jacobs and Azmitia, 1992). In addition, a dysfunction of the 5-HT system is thought to underlie a variety of psychiatric disorders, including anxiety and depression (Arango et al., 2002). Drugs that increase serotonin tone in the brain are the major substances use