Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism
Por:
Padilla-Orozco, Montserrat, Duhne, Mariana, Fuentes-Serrano, Alejandra, Ortega, Aidan, Galarraga, Elvira, BARGAS, JOSE, Lara-Gonzalez, Esther
Publicada:
6 sep 2022
Resumen:
Parkinson's disease is a neurodegenerative ailment generated by the loss
of dopamine in the basal ganglia, mainly in the striatum. The disease
courses with increased striatal levels of acetylcholine, disrupting the
balance among these modulatory transmitters. These modifications disturb
the excitatory and inhibitory balance in the striatal circuitry, as
reflected in the activity of projection striatal neurons. In addition,
changes in the firing pattern of striatal tonically active interneurons
during the disease, including cholinergic interneurons (CINs), are being
searched. Dopamine-depleted striatal circuits exhibit pathological
hyperactivity as compared to controls. One aim of this study was to show
how striatal CINs contribute to this hyperactivity. A second aim was to
show the contribution of extrinsic synaptic inputs to striatal CINs
hyperactivity. Electrophysiological and calcium imaging recordings in
Cre-mice allowed us to evaluate the activity of dozens of identified
CINs with single-cell resolution in ex vivo brain slices. CINs show
hyperactivity with bursts and silences in the dopamine-depleted
striatum. We confirmed that the intrinsic differences between the
activity of control and dopamine-depleted CINs are one source of their
hyperactivity. We also show that a great part of this hyperactivity and
firing pattern change is a product of extrinsic synaptic inputs,
targeting CINs. Both glutamatergic and GABAergic inputs are essential to
sustain hyperactivity. In addition, cholinergic transmission through
nicotinic receptors also participates, suggesting that the joint
activity of CINs drives the phenomenon; since striatal CINs express
nicotinic receptors, not expressed in striatal projection neurons.
Therefore, CINs hyperactivity is the result of changes in intrinsic
properties and excitatory and inhibitory inputs, in addition to the
modification of local circuitry due to cholinergic nicotinic
transmission. We conclude that CINs are the main drivers of the
pathological hyperactivity present in the striatum that is depleted of
dopamine, and this is, in part, a result of extrinsic synaptic inputs.
These results show that CINs may be a main therapeutic target to treat
Parkinson's disease by intervening in their synaptic inputs.
Filiaciones:
Padilla-Orozco, Montserrat:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Div Neurociencias, Mexico City, DF, Mexico
Duhne, Mariana:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Div Neurociencias, Mexico City, DF, Mexico
Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA
Fuentes-Serrano, Alejandra:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Div Neurociencias, Mexico City, DF, Mexico
Ortega, Aidan:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Div Neurociencias, Mexico City, DF, Mexico
Galarraga, Elvira:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Div Neurociencias, Mexico City, DF, Mexico
BARGAS, JOSE:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Div Neurociencias, Mexico City, DF, Mexico
Lara-Gonzalez, Esther:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Div Neurociencias, Mexico City, DF, Mexico
Northwestern Univ, Dept Neurosci, Feinberg Sch Med, Chicago, IL 60611 USA
Green Published, gold, All Open Access; Gold
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