Guest lecture by Tamás F. Freund

Control of Cortical Inhibition and Excitation by Endocannabinoids: Novel
Insights into Anxiety and Epilepsy

Tamás F. Freund
Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.

       Endogenous cannabinoids are thought to be retrograde mediators in several forms of synaptic plasticity. Depolarization of hippocampal pyramidal cells, or a rise in intracellular calcium, evokes a CB1 cannabinoid receptor-mediated short-term depression of GABA release from afferent inhibitory terminals (depolarization-induced suppression of inhibition; DSI). CB1 receptors present on interneuron axons mediate both endo- and exogenous cannabinoid actions on cortical GABAergic transmission and associated cognitive functions or dysfunctions. Most of the CB1-modulated interneurons belong to the CCK-containing basket cells, which receive abundant subcortical input, and express several receptors – in addition to CB1 – that are implicated in anxiety. These features enable CCK-positive interneurons to function as a fine-tuning device for cortical fast oscillations, mediating motivational and emotional impacts.
       On the other hand, cannabinoids are known to suppress glutamatergic EPSCs as well, boutons forming asymmetrical synapses on pyramidal cell spines are equipped with presynaptic CB1 receptors. In addition, diacylglycerol lipase alpha (DGL-a), the synthesizing enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), is present in dendritic spines, postsynaptic to the CB1-expressing terminals, thus confirming that 2-AG produced by DGL-a in spines may be involved in retrograde signaling at glutamatergic synapses. The specific location of DGL-a together with mGluR5 in the perisynaptic annulus raises the possibility that glutamate spillover could activate, via mGluR5, the synthesis and release of 2-AG, which may serve to reduce further glutamate release from the presynaptic terminals. Malfunctioning of this negative feed-back system may be involved in epileptogenesis, since a downregulation of CB1 receptors on glutamatergic terminals is among the most profound molecular changes in lobectomy samples of human epileptic patients observed even before degeneration of CA1 pyramidal cells begins.
       Thus, in the cerebral cortex, endocannabinoids are involved in the presynaptic regulation of both GABAergic and glutamatergic transmission, and malfunctioning of this control machinery is implicated in several brain disorders. Identification of the molecular architecture of this signaling system may shed light on its functional roles, and point to new drug targets in pharmacotherapy.

Selected refs from our own work:
- Freund TF, Katona I.  Perisomatic inhibition. Neuron. 2007 Oct 4;56(1):33-42.

- Makara JK, Katona I, Nyíri G, Németh B, Ledent C, Watanabe M, de Vente J,
Freund TF, Hájos N.  Involvement of nitric oxide in depolarization-induced suppression of inhibition in hippocampal pyramidal cells during activation of cholinergic receptors. J Neurosci. 2007 Sep 19;27(38):10211-22.

- Szabadits E, Cserép C, Ludányi A, Katona I, Gracia-Llanes J, Freund TF, Nyíri
G.  Hippocampal GABAergic synapses possess the molecular machinery for retrograde
nitric oxide signaling.  J Neurosci. 2007 Jul 25;27(30):8101-11.

- Katona I, Urbán GM, Wallace M, Ledent C, Jung KM, Piomelli D, Mackie K, Freund
TF.  Molecular composition of the endocannabinoid system at glutamatergic synapses.
J Neurosci. 2006 May 24;26(21):5628-37.

- Freund TF.  Interneuron Diversity series: Rhythm and mood in perisomatic inhibition.
Trends Neurosci. 2003 Sep;26(9):489-95.

- Freund TF, Katona I, Piomelli D.  Role of endogenous cannabinoids in synaptic signaling.
Physiol Rev. 2003 Jul;83(3):1017-66.