Cognitive deficits in episodic ataxia type 2 mouse models

Abstract

Episodic ataxia type 2 (EA2) is a rare autosomal dominant disorder characterized by motor incoordination, paroxysmal dystonia, vertigo, nystagmus and more recently cognitive deficits. To date over 100 mutations in the CACNA1A gene have been identified in EA2 patients leading to a loss of P/Q-type channel activity, dysfunction of cerebellar Purkinje cells (PC) and motor incoordination. To determine if the cerebellum is contributing to these cognitive deficits, we examined 2 different EA2 mouse models for cognition impairments where CACNA1A was removed specifically from cerebellar Purkinje or granule cells postnatally. Both mutant mouse models showed anxiolytic behavior to lighted, open areas in the open field and light/dark place preference tests but enhanced anxiousness in the novel suppressed feeding test. However, EA2 mice continued to show augmented latencies in the light/dark preference test and when the arena was divided into 2 dark zones in the dark/dark preference test. Moreover, increased latencies were also displayed in the novel object recognition test, indicating that EA2 mice are indecisive and anxious to explore new territories and objects and may have memory recognition deficits. Exposure to a foreign mouse led to deficiencies in attention and sniffing as well as social and genital sniffing were observed. These data suggest that postnatal removal of the P/Q type calcium channel from the cerebellum regulates neuronal activity involved in anxiety, memory, decision making and social interactions. Our EA2 mice will provide a model to identify the mechanisms and therapeutic agents underlying cognitive and psychiatric disorders seen in EA2 patients.

CACNA1Ahaploinsufficiency leads to reduced synaptic function and increased intrinsic excitability

“…Mouse models with Cacna1a loss-of-function variants recapitulate the range of human clinical phenotypes, exhibiting a combination of ataxia, paroxysmal dyskinesia, absence epilepsy, and cognitive deficits. [8][9][10][11][12][13] The motor incoordination of these models, as well as the high expression of CACNA1A in the cerebellum, has led to a thorough investigation of Cav2.1 in cerebellar granule cells and Purkinje cells. At the cellular level, loss-of-function variants lead to a reduced current density of Cav2.1, loss of Purkinje cell pace-making activity, and Purkinje cell axonal swelling.…”

Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1

“…In cerebellar mutant mice, depressive- and anxiety-like behavior and anhedonia on one hand and reduced anxiety on the other hand can be manifested. The first occurs in the case of significant extracerebellar neuropathology, the latter rather in mice with selective cerebellar damage [ 4 , 23 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ].…”

Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1

“…In cerebellar mutant mice, depressive-and anxiety-like behavior and anhedonia on one hand and reduced anxiety on the other hand can manifest. The first occurs in the case of significant extracerebellar neuropathology, the latter rather in mice with selective cerebellar damage [4,23,[48][49][50][51][52][53][54]. While depression and anhedonia would correspond with reduced sucrose preference, stereotypies, perseveration and disinhibited behavior might lead to abundant sucrose intake in some individuals.…”