Hiện tượng giống như tâm thần phân liệt ở chuột thiếu polysialyltransferase ST8SIA2

Brain Structure and Function - Tập 220 - Trang 71-83 - 2013
Tim Kröcher1,2, Kristina Malinovskaja3, Monika Jürgenson3, Anu Aonurm-Helm3, Tamara Zharkovskaya3, Anti Kalda3, Iris Röckle1, Miriam Schiff1, Birgit Weinhold1, Rita Gerardy-Schahn1,2, Herbert Hildebrandt1,2, Alexander Zharkovsky3
1Institute of Cellular Chemistry (OE4330), Hannover Medical School, Hannover, Germany
2Center for Systems Neuroscience Hannover (ZSN), Hannover, Germany
3Department of Pharmacology, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia

Tóm tắt

Sự sửa đổi sau dịch mã của phân tử kết dính tế bào thần kinh (NCAM) bởi axit polysialic (polySia) là điều quan trọng cho sự phát triển của hệ thần kinh và tính linh hoạt của não. Việc gắn kết polySia được xúc tác bởi các enzyme polysialyltransferase (polyST) ST8SIA2 và ST8SIA4, hai enzyme có chức năng khác nhau nhưng cũng có điểm chung trong quá trình phát triển thần kinh và trong não bộ trưởng thành. Một số lượng ngày càng tăng các bằng chứng liên kết mức độ NCAM và polySia bất thường cũng như sự biến đổi trong gen ST8SIA2 với các rối loạn tâm thần, bao gồm tâm thần phân liệt. Để điều tra xem sự thiếu hụt polyST có thể gây ra hiện tượng giống như tâm thần phân liệt hay không, chúng tôi đã đánh giá các chuột St8sia2−/−, St8sia4−/− và những chuột lứa chung với chúng về mặt giải phẫu thần kinh và thực hiện các bài kiểm tra nhận thức và chức năng cảm giác-vận động. Chuột St8sia2−/− nhưng không phải St8sia4−/− cho thấy những gian bên lớn hơn và giảm kích thước của nhân đồi thị đi kèm với một bao trong nhỏ hơn và mô hình sợi kết nối đồi thị và vỏ não rất rối loạn. Mức độ vận chuyển glutamate dạng bọc VGLUT2 giảm cho thấy sự suy yếu trong việc truyền vào đồi thị-vỏ não glutamatergic vào vỏ não trước của chuột St8sia2−/−. Cả hai dòng thiếu polyST đều bị suy giảm trong trí nhớ nhận diện ngắn và dài hạn, nhưng chỉ có chuột St8sia2−/− thể hiện trí nhớ công việc kém và những khiếm khuyết trong ức chế prepulse. Hơn nữa, chỉ có chuột St8sia2−/− cho thấy hành vi không hứng thú và độ nhạy cao đối với sự tăng cường vận động do amphetamine gây ra. Những kết quả này tiết lộ rằng sự giảm polysialylation trong chuột St8sia2−/− dẫn đến sự phát triển não bộ bệnh lý và hành vi giống như tâm thần phân liệt. Do đó, chúng tôi đề xuất rằng sự biến đổi gen trong ST8SIA2 có tiềm năng tạo ra khuynh hướng phát triển thần kinh đối với tâm thần phân liệt.

Từ khóa

#tâm thần phân liệt #polysialyltransferase #ST8SIA2 #mô hình động vật #phát triển thần kinh

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