The Parkinson's Disease-Associated Mutation LRRK2-G2019S Impairs Synaptic Plasticity in Mouse Hippocampus.

Parkinson's disease (PD) is a major movement disorder characterized by the loss of dopamine neurons and formation of Lewy bodies. Clinical and pathological evidence indicates that multiple brain regions are affected in PD in a spatiotemporal manner and are associated with a variety of motor and nonmotor symptoms, including disturbances in mood, executive function, and memory. The common PD-associated gene for leucine-rich repeat kinase, leucine-rich repeat kinase 2 (LRRK2), is highly expressed in brain regions that are involved with nonmotor functions, including the neocortex and hippocampus, but whether mutant LRRK2 contributes to neuronal dysfunction in these regions is unknown. Here, we use bacterial artificial chromosome transgenic mouse models of LRRK2 to explore potential nonmotor mechanisms of PD. Through electrophysiological analysis of the Schaffer collateral-CA1 synapse in dorsal hippocampus, we find that overexpression of LRRK2-G2019S increases basal synaptic efficiency through a postsynaptic mechanism, and disrupts long-term depression. Furthermore, these effects of the G2019S mutation are age dependent and can be normalized by acute inhibition of LRRK2 kinase activity. In contrast, overexpression of wild-type LRRK2 has no effect under the same conditions, suggesting a specific phenotype for the G2019S mutation. These results identify a pathogenic function of LRRK2 in the hippocampus that may contribute to nonmotor symptoms of PD. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is among the most common neurological diseases and is best known for its adverse effects on brain regions that control motor function, resulting in tremor, rigidity, and gait abnormalities. Less well appreciated are the psychiatric symptoms experienced by many PD patients, including depression and memory loss, which do not respond well to currently available treatments for PD. Here, we describe functional effects of a common PD-linked mutation of leucine-rich repeat kinase 2 in the mouse hippocampus, an area of the brain that is responsible for encoding and retaining memories. By providing a potential mechanism for some of the cognitive symptoms produced by this mutation, our findings may lead to novel approaches for the treatment of nonmotor symptoms of PD.

A critical role for IGF-II in memory consolidation and enhancement.

We report that, in the rat, administering insulin-like growth factor II (IGF-II, also known as IGF2) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein ß and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein and glycogen-synthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3ß and increased expression of GluR1 (also known as GRIA1) α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies.

Inhibiting the inhibition: a neuronal network for sound localization in reverberant environments.

The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performed in vivo recordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Using in vitro recordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects.