New Research Uncovers How Parkinson's Affects the Brain: Molecular Insights into Cognitive Impairment

MEDIA ADVISORY  

Journal Name: Proceedings of the National Academy of Sciences (PNAS)

Pub Date: July 5, 2024

Newswise — Bottom Line: A Parkinson’s-causing gene mutation impairs normal dynamic trafficking of a subtype of glutamate receptor at excitatory synapses on one of two major classes of striatal neurons, preventing synaptic strengthening normally required for several cognitive functions that decline in Parkinson’s. The research shows functional vulnerability in a circuit that does not degenerate in Parkinson's and at a young age.

Results: We found that in mice genetically modified to carry a Parkinson’s-causing gene mutation, a subtype of receptor for the neurotransmitter glutamate accumulates abnormally on the cell surface of a class of neurons in the striatum important for attention and other cognitive functions. Normally, a pool of waiting receptors can be rapidly recruited to synapses to dynamically increase synaptic strength, but in the Parkinson’s neurons, these receptors fail to be recruited to synapses under experimental conditions that normally strengthen synaptic responses. Receptors are immobilized or trapped on the cell surface of Parkinson’s neurons compared to control neurons, unable to internalize, externalize, or even transit within the membrane, thus disrupting the molecular basis of synaptic plasticity essential for cognitive and other striatal functions. These results indicate that the Parkinson's mutation exerts a highly selective impact on particular neural circuits and highlight molecular targets that appear to be particularly vulnerable.  

Why the Research Is Interesting: Parkinson's is associated with a higher risk of cognitive impairment and dementia that can severely impact quality of life. Cognitive symptoms include deficits in attention and mental flexibility, among others, and can pre-date the tremors and rigidity used to diagnose the disease. These and other cognitive abilities depend on the capacity of synapses to strengthen and weaken by dynamic addition or removal of neurotransmitter receptors within the synaptic membrane of relevant striatal and other neural circuits. This study investigated a molecular basis for impaired synapse strengthening as a putative basis for impaired cognitive functions of Parkinson’s. Using mice genetically engineered to carry a Parkinson’s-causing gene mutation, the investigators applied high-resolution microscopy, biochemistry and electrophysiology to show that synapses on one type of striatal neurons important for executive function fail to strengthen because a subtype of glutamate receptor accumulates abnormally on the cell surface and become selectively trapped, unable to move in or out of synapses. These actions restrict synaptic strength to a narrow operating range incompatible with dynamic receptor trafficking required for cognitive functions, and consistent with previous studies showing that these Parkinson’s mice display cognitive deficits. Significantly the findings were consistent in developing and mature mice, which if replicated in humans, could be an early sign of cognitive risk, amenable to treatment prior to neural degeneration.

Who:
Dr. Swati Gupta- lead author, Instructor in Neuroscience
Dr. George Huntley- senior corresponding author, Professor of Neuroscience
Dr. Deanna Benson- senior corresponding author, Professor of Neuroscience

When: We examined neurons in developing and young adult mice to model the cognitive risk and impairment that in humans can emerge in the prodromal period of Parkinson’s, which precedes the overt loss of brainstem dopamine neurons and the resulting motor symptoms.

What: We showed that within an identified excitatory neural circuit in striatum, an AMPA-type glutamate receptor is excessively enriched on the surface both within and outside of synapses on the direct-pathway subtype of striatal projection neurons. The receptors are abnormally stable or trapped as they fail to internalize off the surface or to move readily within the plane of the membrane. Receptors also fail to insert into the membrane when stimulated by paradigms that normally strengthen synapses. Thus, glutamate receptors are saturated and immobile at synapses on these striatal neurons, greatly limiting their function.

How: We used genetically engineered mouse models and cellular assays to measure and track the trafficking of glutamate receptors in identified striatal neural circuits and cell populations in both acute brain slices and cultured neurons. To document receptor composition, dynamics and function, we combined super-resolution microscopy, live-cell imaging, electrophysiology and biochemical approaches. Anatomical tracing and genetic tags were used to identify cell types and circuits.

Study Conclusions: The research suggests that impaired dynamic and coordinated membrane trafficking of a subtype of glutamate receptors into and out of striatal synapses on direct-pathway striatal projection neurons underlies impairment in cognitive or other functions in Parkinson’s.

Paper Title:  Parkinson’s-linked LRRK2-G2019S derails AMPAR trafficking, mobility and composition in striatum with cell-type and subunit specificity

To request a copy of the paper or to schedule an interview with Dr. Deanna Benson and Dr. George Huntley, please contact Mount Sinai’s Director of Media and Public Affairs, Elizabeth Dowling, at [email protected] or at 212 241-9200.

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