Molecular dissection of the ventral subiculum – nucleus accumbens projection circuit.

The hyperactivity of the ventral subiculum – nucleus accumbens circuit has been implicated as a major cause of dopamine dysregulation that is associated with drug addiction and schizophrenia. The ventral subiculum is populated by two distinct glutamatergic principle neurons, termed burst- and regular-spiking, that synapse onto two main populations of postsynaptic  medium spiny neurons (MSNs) in the nucleus accumbens, identified by their expression of dopamine type 1 receptor or dopamine type 2 receptor (D1R and D2R MSNs, respectively). Our enthusiasm to perform a molecular dissection of this circuit, initially in the context of Nrxn3, is bolstered by the recent findings that, the ventral subiculum provides the most robust excitatory input into relative to other bain regions, which implies that synaptic dysfunction in this projection pathway can result in significant alterations in dopamine levels in the brain. Moreover, our recent preliminary data, using circuitry tracing viruses to identify functional connectivity between the ventral subiculum and nucleus accumbens and electrophysiology in Nrxn3 mutant mice, revealed that 1. Functional synapses made by ventral subicular output in the nucleus accumbens are almost exclusively found in the medial shell (Fig. 2) and that, following the genetic manipulation of Nrxn3, excitatory transmission in the medial shell is significantly altered (data not shown). These findings suggest that ventral subicular input into the nucleus accumbens might play a significant role in regulating dopamine levels via the reward circuitry. Yet, despite the mounting evidence implicating the ventral subiculum in dopamine dysregulation, little is known regarding the distribution of RS and BS connectivity with D1R and D2R medium spiny neurons, the cell-type specific synaptic properties and the functional role of presynaptic Nrxn3 in presynaptic RS and BS neurons are unknown. We are investigating how Nrxn3 shapes cell-type and synapse-specific connectivity and function in this projection circuit.

Figure 1. Cartoon diagram of the ventral subiculum–nucleus accumbens projection circuit. regular (RS) and burst (BS) spiking neurons protect to and innervate D1R and D2R MSNs in an uncharacterized pattern. Glutamatergic input onto D1R and D2R MSNs from ventral subicular axons is uncharacterized. ? represent uncharacterized properties of this circuit.

Figure 2. Functional circuit tracing using Synaptotag virus (AAV phSYN mCherry-IRES-synaptobrevin2-GFP to label presynaptic active zones (green). Synaptotag was injected into the ventral subiculum at P21 and imaged on P50. Tracing revealed that the ventral subiculum almost exclusively makes functional synapses in the medial shell of the nucleus accumbens.