The cellular basis of depressive disorders is poorly understood1. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (i.e. disappointment or anticipation of a negative outcome)2, 3, 4. LHb neurons project to and modulate dopamine-rich regions such as the ventral-tegmental area (VTA)2, 5 that control reward-seeking behavior6 and participate in depressive disorders7. Here we show in two learned helplessness models of depression that excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal’s helplessness behavior and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective on depressed patients8, 9, dramatically suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behavior in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively-valenced events. Its hyperactivity is associated with depression. While enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that GABA is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted towards reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this remarkable form of transmission may be important for determining the impact of negative life events on mood and behavior.

Upon entry into the central nervous system (CNS), serum insulin-like growth factor-1 (IGF-I) modulates neuronal growth, survival, and excitability. Yet mechanisms that trigger IGF-I entry across the blood-brain barrier remain unclear. We show that neuronal activity elicited by electrical, sensory, or behavioral stimulation increases IGF-I input in activated regions. Entrance of serum IGF-I is triggered by diffusible messengers (i.e., ATP, arachidonic acid derivatives) released during neurovascular coupling. These messengers stimulate matrix metalloproteinase-9, leading to cleavage of the IGF binding protein-3 (IGFBP-3). Cleavage of IGFBP-3 allows the passage of serum IGF-I into the CNS through an interaction with the endothelial transporter lipoprotein related receptor 1. Activity-dependent entrance of serum IGF-I into the CNS may help to explain disparate observations such as proneurogenic effects of epilepsy, rehabilitatory effects of neural stimulation, and modulatory effects of blood flow on brain activity.

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N- and P/Q-type voltage dependent calcium channels (VDCCs) mediate transmitter release at neonatal rat neuromuscular junction (NMJ). Thus the neonatal NMJ allows an examination of the coupling of different subtypes of VDCCs to the release process at a single synapse. We studied calcium dependence of transmitter release mediated by each channel by blocking with omega-conotoxin GVIA the N-type channel or with omega-agatoxin IVA the P/Q-type channel while changing the extracellular calcium concentration ([Ca2+]o). Transmitter release mediated by P/Q-type VDCCs showed steeper calcium dependence than N-type mediated release (average slope 3.6 +/- 0.09 vs. 2.6 +/- 0.03, respectively). Loading the nerve terminals with 10 microm BAPTA-AM in the extracellular solution reduced transmitter release and occluded the blocking effect of omega-conotoxin GVIA (blockade -2 +/- 9%) without affecting the action of omega-agatoxin IVA (blockade 85 +/- 4%). Both VDCC blockers were able to reduce the amount of facilitation produced by double-pulse stimulation. In these conditions facilitation was restored by increasing [Ca2+]o. The facilitation index (fi) was also reduced by loading nerve terminals with 10 microm BAPTA-AM (fi = 1.2 +/- 0.1). The control fi was 2.5 +/- 0.1. These results show that P/Q-type VDCCs were more efficiently coupled to neurotransmitter release than were N-type VDCCs at the neonatal neuromuscular junction. This difference could be accounted for by a differential location of these channels at the release site. In addition, our results indicate that space-time overlapping of calcium domains was required for facilitation.

Different types of voltage-activated Ca(2+) channels have been established based on their molecular structure and pharmacological and biophysical properties. One of them, the P/Q-type, is the main channel involved in nerve-evoked neurotransmitter release at neuromuscular junctions and the immunological target in Eaton-Lambert Syndrome. At adult neuromuscular junctions, L- and N-type Ca(2+) channels become involved in transmitter release only under certain experimental or pathological conditions. In contrast, at neonatal rat neuromuscular junctions, nerve-evoked synaptic transmission depends jointly on both N- and P/Q-type channels. Synaptic transmission at neuromuscular junctions of the ataxic P/Q-type Ca(2+) channel knockout mice is also dependent on two different types of channels, N- and R-type. At both neonatal and P/Q knockout junctions, the K(+)-evoked increase in miniature endplate potential frequency was not affected by N-type channel blockers, but strongly reduced by both P/Q- and R-type channel blockers. These differences could be accounted for by a differential location of the channels at the release site, being either P/Q- or R-type Ca(2+) channels located closer to the release site than N-type Ca(2+) channels. Thus, Ca(2+) channels may be recruited to mediate neurotransmitter release where P/Q-type channels seem to be the most suited type of Ca(2+) channel to mediate exocytosis at neuromuscular junctions.

The Lateral Habenula (LHb) is a small brain structure that codifies negative motivational value and has been related to major depression. It has been shown recently that LHb activation is sufficient to induce aversive associative learning; however the key question about whether LHb activation is required for an aversive memory to be formed has not been addressed. In this article we studied the function of the LHb in memory formation using the Inhibitory Avoidance task (IA). We found that LHb inactivation during IA training does not disrupt memory when assessed 24 h after, but abolishes it 7 days later, indicating that LHb activity during memory acquisition is not necessary for memory formation, but regulates its temporal stability. These effects suggest that LHb inactivation modifies subjective perception of the training experience.