Development- and experience-dependent plasticity in the dorsomedial habenula

Abstract

Of the two major subdivisions of the habenula, the medial and lateral nuclei, the medial habenula is the least understood in terms of synaptic transmission, intrinsic properties and plasticity. The medial habenula (MHb) is composed of glutamatergic neurons which receive the majority of their inputs from the septal region and project predominantly to the interpeduncular nucleus (IPN). To understand the synaptic transmission, we studied both glutamatergic and GABAergic synaptic transmission in the dorsal region of the medial habenula (dMHb). While glutamatergic transmission dominates during early development, an attenuation of glutamatergic transmission and an enhancement of GABAergic transmission occur during development leading into adulthood. Furthermore, as reported previously, GABAA receptor-mediated transmission is excitatory in the adult dMHb, which is consistent with the reduced expression of the K-Cl co-transporter KCC2. Given the potential role of the dMHb in aversive behaviors, we examined whether fear conditioning or exposure to foot shock affects excitability in dMHb neurons. We observed a suppression of the excitability of dMHb neurons in mice that either underwent fear conditioning or were exposed to foot shock. Furthermore, we observed a suppression of GABAergic but not glutamatergic transmission in the dMHb neurons following fear conditioning. These results suggest that aversive experience produces a suppression of the dMHb neuronal activity. Given that the medial habenula is upstream of the median raphe nucleus which is believed to be involved in the negative regulation of aversive memory, the suppression of dMHb neurons following an aversive experience might play a role in strengthening of aversive memories.

Functional Principles of Posterior Septal Inputs to the Medial Habenula

“…Our results may also be explained by the emerging complexity of afferent synaptic excitation to the MHb. Defying expectations, several groups have indeed reported that GABAergic afferences increase, rather than decrease, neuronal firing in the MHb ( Kim and Chung, 2007 , Choi et al., 2016 , Koppensteiner et al., 2016 ). Similarly to glutamatergic fibers, GABAergic axons impinging onto MHb cells originate in septal nuclei ( Qin and Luo, 2009 ).…”

A Cooperative Mechanism Involving Ca2+-Permeable AMPA Receptors and Retrograde Activation of GABAB Receptors in Interpeduncular Nucleus Plasticity

“…Furthermore, our results suggest a critical role of the mechanisms underlying the activity-dependent MHb-IPN plasticity in fear regulation. Our recent work showed that aversive experiences suppress the excitability of MHb neurons (Koppensteiner et al, 2016), which might cause an impairment of the GABA B receptor-dependent pre-synaptic facilitation necessary for MHb-IPN plasticity. Future studies will be necessary to understand whether and how fear extinction modifies the excitability of MHb neurons and hence activity-dependent glutamate release onto the IPN neurons.…”

“…Apart from its unique topographical organization and co-release mechanisms, the MHb-IPN pathway is characterized by distinct physiological properties, particularly the excitatory role of the GABA A receptors in MHb neurons, due to a lack of the K-Cl co-transporter KCC2 (Kim and Chung, 2007; Koppensteiner et al, 2016). Furthermore, GABA B receptors on the ventral MHb terminals also show excitatory effects, as their activation results in enhanced glutamate release by an augmentation of Ca 2+ entry through Cav2.3 channels (Zhang et al, 2016).…”

GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals

“…The medial habenula (MHb) is an epithalamic structure that exclusively projects to the interpeduncular nucleus (IPN), with the dorsal MHb projecting to the lateral IPN and the ventral MHb projecting to the rostral and central subnuclei of the IPN ( Figure 1A ). This pathway is involved in various behaviors, including nicotine addiction and aversion ( Agetsuma et al, 2010 ; Koppensteiner et al, 2016 ; Koppensteiner et al, 2017 ; Melani et al, 2019 ; Zhang et al, 2016 ; Zhao-Shea et al, 2013 ). A striking property of the MHb-IPN pathway is the prominent presynaptic localization of the R-type voltage-gated Ca 2+ channel 2.3 (Cav2.3), a channel mainly located in postsynaptic elements in other brain areas ( Parajuli et al, 2012 ).…”