BDNF and other neurotrophins (NTs) have widespread and powerful roles in the mammalian nervous system,
and are thought to be involved in synaptic plasticity, learning, and memory, as well as in a number of psychiatric
and neurological disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Rett
syndrome, drug addiction, schizophrenia, and depression. However, how NTs function at the cellular and
synaptic levels is not well understood. For example, it is not clear whether NTs are released from or act on the
pre- or postsynaptic neuron, or whether and how multiple mammalian NTs interact at a single synapse. Aplysia
sensory-motor neuron cell culture is an ideal system for addressing these types of questions. We had previously
identified an Aplysia BDNF ortholog (ApNT) and its Trk receptor (ApTrk) and found that they are important for
the induction of long-term facilitation (LTF) and consolidation of short-term (ST) to early intermediate-term (IT)
facilitation. Our results do not support the simple linear cascade that we and others had expected, but rather
reveal that ApNT plays surprising roles in two synaptic feedback loops: [1] as an autocrine signal in a presynaptic
positive feedback loop that amplifies the molecules required, and [2] as both an anterograde and retrograde
signal in a transynaptic feedback loop that coordinates mechanisms in the presynaptic and postsynaptic
compartments. These loops provide novel mechanisms for consolidation of learning-related plasticity that could
well contribute more generally. We now propose to extend those studies in three new directions:
1. The roles of ApNT and ApTrk in consolidation of long-term plasticity. We will investigate the roles of ApNT
and ApTrk in consolidation of early IT to late IT and LT plasticity. We will also explore possible functions of the
feedback loops, and investigate the roles of ApNT and ApTrk in gene regulation and the assembly of pre- and
postsynaptic components in a synaptic growth cascade.
2. The roles of pro and mature isoforms of ApNT. Like other neurotrophins ApNT has pro and mature forms
whose relative functions are unclear. Investigating the roles of those isoforms of a NT is much easier in the
Aplysia system, which only has a single neurotrophin. Our preliminary results suggest the hypothesis that
release of the mature form from sensory neurons may act as an autocrine signal that contributes to induction of
facilitation, whereas release of the pro form from motor neurons may act as a retrograde signal that contributes
to stabilization, perhaps by interacting with CPEB or PKM. We will test that hypothesis in several ways.
3. The causal roles of ApNT and ApTrk and their integration with other mechanisms during behavioral learning.
The exact roles of neurotrophins in behavioral learning and memory are also unclear. To address that question,
we have been studying mechanisms of simple forms of learning under physiological conditions in a reduced
preparation of the Aplysia siphon withdrawal reflex. We will now use that preparation to explore the causal roles of
ApNT and ApTrk and their integration with other cellular and molecular mechanisms during behavioral learning.