Delivery of different genes into presynaptic and postsynaptic neocortical neurons connected by a BDNF-TrkB synapse.

Brain-Derived Neurotrophic Factor (BDNF) signaling through TrkB receptors has important roles in synapse formation, synaptic plasticity, learning, and specific diseases. However, it is challenging to relate BDNF-TrkB synapses to circuit physiology or learning, as BDNF-TrkB synapses are embedded in complex circuits that contain numerous neuron and synapse types. Thus, analyzing the physiology of neurons connected by BDNF-TrkB synapses would be advanced by a technology to deliver different genes into presynaptic and postsynaptic neurons, connected by a BDNF-TrkB synapse. Here, we report selective gene transfer across BDNF-TrkB synapses: The model system was the large projection from rat postrhinal to perirhinal cortex. The first gene transfer, into presynaptic neurons in postrhinal cortex, used a virus vector and standard gene transfer procedures. This vector expresses a synthetic peptide neurotransmitter composed of three domains, a dense core vesicle sorting domain, BDNF, and the His tag. Upon release, this peptide neurotransmitter binds to TrkB receptors on postsynaptic neurons. The second gene transfer, into connected postsynaptic neurons in perirhinal cortex, uses antibody-mediated, targeted gene transfer and an anti-His tag antibody, as the synthetic peptide neurotransmitter contains the His tag. Confocal microscope images showed that using untargeted gene transfer, only 10-15% of the transduced presynaptic axons were proximal to a transduced postsynaptic dendrite. But using targeted gene transfer, ∼70% of the transduced presynaptic axons were proximal to a transduced postsynaptic dendrite. This technology may support studies on the roles of neurons connected by BDNF-TrkB synapses in circuit physiology and learning.