Healthy / Parkinson’s disease comparison panels, Direct pathway PD data table (SNc / D1 MSNs / GPi&SNR / thalamus / Cortex), Indirect pathway data table (D2 MSNs / GPe / STN / GPi&SNR / thalamus), DBS / GAD note, Input / Output diagrams, PD / HD cause-direct-indirect-consequence table, In HD subsection (D2 MSN / D1 MSN), Mhtt synaptic notes, Hypokinetic Sx

Healthy vs Parkinson’s disease (panel labels)

(Associative) motor cortex → Striatum (Thalamus) → Substantia nigra pars compacta / Subthalamic nucleus / Globus pallidus internus
Edge labels: GABA, +Glutamate

In PD, (↓ GABA-erigic input from striatum →) disinhibition at STN and Gpi leads to increased inhibition at thalamus (slide11: 실제로 ↑ GABA_THAL) leading to reduced motor activity (Univ of florida semimechanistic efficacy model).
원래 thalamus 에서 movement initation 의 green light 줌!, 근데 PD 에선, the thalamus is kept in an overly inhibited state.
Change in GABA_Thl is the driver for clinical symptoms

		SNc	(D1 receptor-containing) (GABAergic) MSNs in the (medial) dorsal striatum	GPi & SNR	thalamus	Cortex
(normally) 다음 단계에 대한 작용 방향성 (위그림)		+	-	-	+
		서	스	지	쌀	코
PD 예측		↓	↓	↑	↓
PD findings (in): firing (McGregor and Nelson 2019, PMID)	MPTP monkeys	(Cui, 2021 #1415)	(D2? receptor-containing) (GABAergic) MSNs in the (lateral) dorsal striatum	GPe 에서 Npas1 cells 들이 overactivation 되어있다.	= (in NHP, (Pessiglione et al. 2005, PMID), ↓ by microelecrode-guided functional stereotactic neurosurgery (Molnar al. 2005, PMID 15703231)
	PD patients		↑ ((Singh, 2016 #1520)), =	↑
	Mice
	rat		↓
DBS				GPi 를 inhibition

	(Direct 대비 아래 노란배경 둘이 추가) GPe neurons (direct 대비 이 inhibitory 가 하나 추가되었으니 이후 과정이 역)	STN	GPi & SNR	thalamus
			지	쌀
Circuit 내 작용		↑
정상인		↓
In PD		↑ (disinhibited) 그래서 overactivated, 그래서 여기에 DBS 함.
		↓
DBS (& subthalamotomy)	이것의 기능을 Supplement (cf. 실제 주입은 STN에)
GAD (glutamic acid decarboxylase) GT (GAD is the rate-limiting enzyme for GABA production)

미시 process
Cortex → ↑ D2 in Striatum → ↓ Gpe → ↓ STN → ↑ SNR (SNR 대신 GPi 로 간다는 설명도 있음, review basic good) → ↓ Thalamus → ↑ Cx
거시 process
Striatum 이 활성화되면 → STN 을 억제하는 Gpe 를 억제하므로 (쎰쎰이 되어) STN 이 활성화 → SNR 이 활성화 → 원래 Thalamus 는 Cx 를 활성화시키는데 이를 억제하므로 최종적으로 Cx 가 억제됨.
overall, inhibit thalamus and thus cortex
평소: 이 indirect pathway 가 억제되어 있음 (HOW? By cortex?).
PD: ↓ SNc → [indirect pathway 의 억제를 못 함] → thalamus is kept inhibited.

CORTEX
Striatum (+D1 / D2)
GPi / SNR / SNc / GPE
STN OFF
Thalamus
Key: Excitatory / Inhibitory
Caption (blue panel): ↑ release of GABA onto the GP to inhibits its inhibitory affects on the thalamic nucleus. → thalamocortical pathways excited and transmits motor neuron signals to the cerebral cx to allow the initiation of movement, this is absent in PD

Input: Cortex / Thalamus / SN → striatum, edge label 'corticostriatal pathway': glutamatergic, excitatory
Output: SNpr Internal GP → Thalamus → cortex

	cause	Direct	Indirect	consequence
PD	SNc 망가져서	↓ (핵심)	↑	↓ motor initiation
HD	특히 Gpe 로 가는 Str 망가져서, 즉 indirect pathway 가 망가져서	↑	↓ (핵심)	↑ motor function

주 View
- D2 MSN 이 주로 죽는다, (whereas MSNs expressing SP, projecting to the GPi are relatively spared, although the SP-containing projections to the SNr are more severely affected than the SP-containing to the GPi (André et al. 2010, PMID PMC3118459))
최근 변형 view
- D1 MSN 도 vulnerable 하다
  - 그러나 neuroprotective mechanism 이 있는건지, D2 MSN 보다 덜 죽는다.(Cepeda et al. 2014, PMID PMC4409123)
MSN in Striatum 이 죽으므로 → 위의 정상적인 억제작용이 안 되어서,
- 1. direct pathway 만 활성화되어서 motor hyperactivity 됨.
- 1. striatum 에서 받을 놈이 없으니 corticostrital pathway 가 보상적으로 활성화

ASN NEURO 2(2):art:e00033 doi:10.1042/AN20090058, 2010

Mhtt 이 길기 때문에 → ↑ glutamate release, ↑ synaptic response, ↑ amplitude spontaneous synaptic events → collapse of spines on postsynaptic MSSNs → ↑ membrane input
Hypokinetic Sx: parkinsonism such as bradykinesia and rigidy

location	transcription	uncertainty
Mhtt note	`collapse of spines on postsynaptic MSSNs → ↑ membrane input`	`MSSNs` could be `MSNs` (Medium Spiny Neurons); preserved verbatim.