Modulatory actions of the kynurenine pathway metabolite Xanthurenic Acid (XA) on firing patterns of thalamic neurones in vitro and in vivo.

SLS Dunn1, CS Copeland1, SA Neale2, TE Salt1. 1UCL Institute of Ophthalmology, London, EC1V 9EL, UK, 2Neurexpert Ltd, London, EC1V 2NX, UK

Xanthurenic Acid (XA) is an endogenous kynurenine metabolite that has been shown to have various neuro-active properties, including inhibition of Vesicular Glutamate Transport (VGLUT) and interaction with metabotropic glutamate (mGlu) receptors [1,3]. Disturbances in kynurenine metabolism may contribute to neurological and neuropsychiatric disease processes [5], and XA can be taken up and released from rodent brain [2]. Thalamic burst firing and synchrony is thought to be important in cognition and attention, sleep, and absence epilepsy [4]. We have therefore investigated the possibility that XA may modulate thalamic burst firing in order to determine whether changes in XA levels could contribute to disease processes.

Extracellular single neurone or multi-neurone recordings were made from the ventrobasal thalamus (VB) using glass micropipettes (5MΩ) in horizontal slices of c57/blk6 mouse (>4 weeks old) brains in vitro. Electrical stimulation of the medial lemniscus was used to activate sensory drivers to VB or stimulation of the internal capsule / thalamic reticular nucleus (TRN) was used to activate TRN outputs to VB. Both of these stimulation pathways resulted in patterns of burst firing following an initial 100-400ms duration inhibition of VB neurones. Bath application of XA (1-3mM) to thalamic slices caused a concentration-related increase in the firing of action potentials that occurred following stimulation of either the medial lemniscus (3mM XA: 278 ±104% of control, n=5, P<0.05, Wilcoxon Signed Rank test) or the internal capsule (3mM XA: 183 ±15% of control, n=7, P<0.05). This increase in action potential firing could be accounted for by an increase in the number of action potential bursts rather than a change in the action potential content of bursts. In order to further investigate the action of XA in VB, extracellular recordings were made in vivo with multi-barrel iontophoretic electrodes from single vibrissae-responsive VB neurones of urethane-anaesthetised (1.2g/kg urethane, I.P.) adult Wistar rats. Procedures were Home Office (UK) approved and accorded with the Animals (Scientific Procedures) Act 1986. Iontophoretically applied XA did not significantly alter the total number of spikes evoked by vibrissae stimulation (91 ±5% when compared to control), but did significantly alter the proportion of spikes in bursts (control: 63 ±8% of spikes in bursts; XA: 43 ±9% of spikes in bursts; n=6, P<0.05).

These results show that XA can modify burst firing of thalamic neurones both in vivo and in vitro. The mechanism by which this occurs is still to be determined, and is likely to be affected by the state of the VB-TRN network. Nevertheless, this opens the possibility that disturbances in kynurenine metabolism that might occur in disease states could cause changes in thalamic function. Such functional changes could contribute to disease symptoms in neurological and psychiatric diseases such as schizophrenia.

1. Fazio, F., et al. (2011). Current Neuropharmacology 9 (Suppl 1): 19.

2. Gobaille, S., et al. (2008). Journal of Neurochemistry 105: 982-993.

3. Neale, S.A., et al. (2013). Neuropsychopharmacology 38: 1060-1067.

4. Pinault, D. (2011). Schizophrenia Bulletin 37: 238-243.

5. Stone, T.W. & L.G. Darlington (2013). British Journal of Pharmacology 169: 1211-1227.