Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala

Abstract

The basolateral amygdala (BLA) is a key site for crossmodal association of sensory stimuli and an important relay in the neural circuitry of emotion. Indeed, the BLA receives substantial glutamatergic inputs from multiple brain regions including the prefrontal cortex and thalamic nuclei. Modulation of glutamatergic transmission in the BLA regulates stress- and anxiety-related behaviors. Serotonin (5-HT) also plays an important role in regulating stress-related behavior through activation of both pre- and postsynaptic 5-HT receptors. Multiple 5-HT receptors are expressed in the BLA, where 5-HT has been reported to modulate glutamatergic transmission. However, the 5-HT receptor subtype mediating this effect is not yet clear. The aim of this study was to use patch-clamp recordings from BLA neurons in an ex vivo slice preparation to examine 1) the effect of 5-HT on extrinsic sensory inputs, and 2) to determine if any pathway specificity exists in 5-HT regulation of glutamatergic transmission. Two independent input pathways into the BLA were stimulated: the external capsule to mimic cortical input, and the internal capsule to mimic thalamic input. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) induced by stimulation of both pathways. The decrease was associated with an increase in the paired-pulse ratio and coefficient of variation of eEPSC amplitude, suggesting 5-HT acts presynaptically. Moreover, the effect of 5-HT in both pathways was mimicked by the selective 5-HT1B receptor agonist CP93129, but not by the 5-HT1A receptor agonist 8-OH DPAT. Similarly the effect of exogenous 5-HT was blocked by the 5-HT1B receptor antagonist GR55562, but not affected by the 5-HT1A receptor antagonist WAY 100635 or the 5-HT2 receptor antagonists pirenperone and MDL 100907. Together these data suggest 5-HT gates cortical and thalamic glutamatergic inputs into the BLA by activating presynaptic 5-HT1B receptors.

<p>Investigating the Role of Glutamate in Obsessive-Compulsive Disorder: Current Perspectives</p>

“…Pre-synaptic 5HT1b receptors are involved in the gating of cortical and thalamic glutamate inputs onto principal neurons of basolateral amygdala (BLA), a key region implicated in the circuitry of emotion regulation, shown to be impaired in OCD. 50 Some clinical evidence is derived from studies that have shown selective improvement in compulsive behaviours upon the addition of topiramate, N-acetyl cysteine (NAC),and lamotrigine. [51][52][53][54] There appears to be a wider, more complex pharmacogenetic role for glutamate in treatment response in OCD.…”

“…Glutamate may have a role in altering the treatment response to OCD in connection with serotonin receptors, which are now shown to be involved in controlling cortical and thalamic glutamatergic input to basolateral amygdala. 50 Overall, glutamatergic modulation might offer novel perspectives in understanding the pathophysiology of compulsivity. Such an enhanced perspective has the potential to widen the horizons of treatment options for the condition.…”

Cell adhesion factors during adolescence support amygdalo-cortical connections and flexible action later in life

“…Brains were extracted and sectioned using a vibrating microtome (Leica) into 300 µm sections. Sections containing the BLA were incubated in 95%O2/5%CO2 oxygenated 32°C sectioning ACSF for hr before recording (for details, see 66 ).…”

Cortico-Limbic Interactions Mediate Adaptive and Maladaptive Responses Relevant to Psychopathology

“…The BLA receives information about the environment from the rest of the brain, such as the PFC, auditory, visual, and somatosensory cortices, the thalamus, and the hippocampus, and it is a key amygdalar structure in cued threat conditioning (77,(83)(84)(85)(86)(87). BLA nuclei send glutamatergic projections to the Ce, as well as other brain regions, and transmit the learned associations between cue, context, and threat to the Ce (Figure 1D) (70,73,(88)(89)(90).…”